bluuebunny/crossref_metadata_2025 huggingface dataset:
The phase behavior of two-dimensional symmetrical mixtures
Authors: Materniak S. , Patrykiejew A. , Sokołowski S.
Published: December 2010

Using Monte Carlo simulation methods in the grand canonical and semigrand canonical ensembles, we study the phase behavior of two-dimensional symmetrical binary mixtures of Lennard-Jones particles. We discuss the interplay between the demixing transition in a liquid and the freezing in detail. Phase diagrams for several systems characterized by different parameters describing interactions in the system are presented. It is explicitly demonstrated that different scenarios involving demixing and freezing transitions, described in our earlier paper [A. Patrykiejew and S. Sokołowski, Phys. Rev. E, 81, 012501 (2010)], are possible. In one class of systems, the λ-line representing a continuous demixing transition in a liquid phase starts at the liquid side of either the vapor–liquid or liquid–solid coexistence. The second class involves the systems in which the λ-line begins at the liquid side of the vapor–liquid coexistence, in the lower critical end point, and then terminates at the liquid side of the liquid–solid coexistence, in the upper critical end point. It is also shown that in such systems the solid phase may undergo a demixing transition at the temperature above the upper critical end point.
Macroscopic facilitation of glassy relaxation kinetics: Ultrastable glass films with frontlike thermal response
Authors: Léonard Sébastien , Harrowell Peter
Published: December 2010

The recent experimental fabrication of ultrastable glass films, via vapor deposition [Swallen et al., Science 315, 353 (2007)] and the observation of frontlike response to the annealing of these films [Swallen et al., Phys. Rev. Lett. 102, 065503 (2009)] have raised important questions about the possibility of manipulating the properties of glass films and addressing fundamental questions about kinetics and thermodynamics of amorphous materials. Central to both of these issues is the need to establish the essential physics that governs the formation of the ultrastable films and their subsequent response. In this paper, we demonstrate that a generic model of glassy dynamics can account for the formation of ultrastable films, the associated enhancement of relaxation rates by a factor of 105, the observation of frontlike response to temperature jumps and the temperature dependence of the front velocity.
New large volume hydrothermal reaction cell for studying chemical processes under supercritical hydrothermal conditions using time-resolved in situ neutron diffraction
Authors: Ok Kang Min , O’Hare Dermot , Smith Ronald I. , Chowdhury Mohammed , Fikremariam Hanna
Published: December 2010

The design and testing of a new large volume Inconel pressure cell for the in situ study of supercritical hydrothermal syntheses using time-resolved neutron diffraction is introduced for the first time. The commissioning of this new cell is demonstrated by the measurement of the time-of-flight neutron diffraction pattern for TiO2 (Anatase) in supercritical D2O on the POLARIS diffractometer at the United Kingdom's pulsed spallation neutron source, ISIS, Rutherford Appleton Laboratory. The sample can be studied over a wide range of temperatures (25–450 °C) and pressures (1–355 bar). This novel apparatus will now enable us to study the kinetics and mechanisms of chemical syntheses under extreme environments such as supercritical water, and in particular to study the crystallization of a variety of technologically important inorganic materials.
Entanglement of charge transfer, hole doping, exchange interaction, and octahedron tilting angle and their influence on the conductivity of La1−xSrxFe0.75Ni0.25O3−δ: A combination of x-ray spectroscopy and diffraction
Authors: Erat Selma , Braun Artur , Piamonteze Cinthia , Liu Zhi , Ovalle Alejandro , Schindler Hansjürgen , Graule Thomas , Gauckler Ludwig J.
Published: December 2010

Substitution of La by Sr in the 25% Ni doped charge transfer insulator LaFeO3 leads to structural changes that inflect the electrical conductivity, which is caused by small polaron hopping via charge transfer and exchange interactions. The substitution forms electron holes and causes a structural transition from orthorhombic to rhombohedral symmetry, and then to cubic symmetry. The structural crossover is accompanied by a crossover from the Fe3+–O2−–Fe3+ superexchange interaction to the Fe3+–O2−–Fe4+ double exchange interaction in the course of substitution, as evidenced by a considerable increase in the conductivity at ambient temperature. The charge transfer and exchange interactions depend on the superexchange angle, which approaches 180° upon increasing Sr concentration. An increase in superexchange angle leads to an increase in overlapping between the O 2p and the Fe/Ni 3d orbitals.
In-depth profiling of electron trap states in silicon-on-insulator layers and local mechanical stress near the silicon-on-insulator/buried oxide interface in separation-by-implanted-oxygen wafers
Authors: Nakajima Yoshikata , Toda Takahiro , Hanajiri Tatsuro , Toyabe Toru , Sugano Takuo
Published: December 2010

In-depth profiling of electron trap states in silicon-on-insulator (SOI) layers of separation-by-implanted-oxygen (SIMOX) wafers was carried out using the drain current-gate voltage characteristics of metal-oxide-semiconductor field-effect transistors (MOSFETs) with different SOI thicknesses, and the density of electron trap states in a gate oxide (GOX) layer thermally grown on them was measured using the gate tunneling current-gate voltage characteristics of MOSFETs. It was found that in-depth profiles of electron trap states in SOI layers have a broad peak at around 25 nm from the SOI/buried oxide (BOX) interface, and that the density of electron trap states in a GOX layer grown on the 25-nm-thick SOI layer reaches a maximum there. A morphology study using Auger electron spectroscopy and Raman spectroscopic study revealed a correlation among the density of trap states in an SOI layer, roughness, and local mechanical stress near the SOI/BOX interface. This correlation is understood to imply that local mechanical stress near the SOI/BOX interface, which is induced by roughness at the interface peculiar to the SIMOX process, enhances the generation of structural defects and resultant electron trap states in the SOI layer of a SIMOX wafer.
Investigation of nonlinear optical properties of gold nanograins embedded in indium oxide films by reflection Z-scan using continuous laser
Authors: Henari F. Z. , Dakhel A. A.
Published: December 2010

Nanograins of gold-embedded in indium oxide thin films were fabricated by vacuum evaporation on silicon substrate. The gold concentrations were 3, 5, and 7 at. % as measured by x-ray fluorescence method. The x-ray diffraction results reveal that pure gold was crystallized into nanograins embedded in the indium oxide medium. The nonlinear optical properties of films on silicon substrate were investigated by reflection z-scan technique, using cw laser at 514 nm. Measurements of nonlinear refractive index and nonlinear absorption coefficient on these films are reported and the mechanism responsible for the process of optical nonlinearities is discussed.
A nonlinear transient constitutive model with eddy current effects for giant magnetostrictive materials
Authors: Wang Tian-Zhong , Zhou You-He
Published: December 2010

In this article, the dynamic magnetostrictive effect of giant magnetostrictive materials is studied and a novel general nonlinear transient constitutive model is established, in which the eddy current effects are incorporated. The validity and reliability of the obtained nonlinear transient constitutive model are verified by comparing its predicted results with existing experimental data. The excellent agreements between predicted results and experimental data indicate that the nonlinear transient constitutive model with eddy current effects can accurately capture frequency-dependent hysteretic behavior exhibited by giant magnetostrictive materials under different applied magnetic field amplitudes and frequencies. Moreover, the obtained constitutive model can also effectively capture the nonlinear magnetic-elastic-thermal coupling effect of giant magnetostrictive materials, since the stress and temperature-dependencies are incorporated in the nonlinear transient constitutive model. In such a case, the influences of exciting frequency and temperature on the dynamic magnetostrictive effect of giant magnetostrictive materials are discussed in detail by using this nonlinear transient constitutive model. The numerical simulation results evidence the notable dependences of dynamic magnetostrictive effect on exciting frequency and temperature, which indicate that the effects of eddy current and temperature on the dynamic magnetostrictive effect can not be ignored. Therefore, the nonlinear transient constitutive model with eddy current effects established in this article has great practical value for both theoretical researches and engineering applications of giant magnetostrictive materials.
Magnetization reversal in magnetic half-balls influenced by shape perturbations
Authors: Blachowicz T. , Ehrmann née Tillmanns A. , Steblinski P. , Pawela L.
Published: December 2010

The magnetization reversal dynamics of three-dimensional (3D) ferromagnetic permalloy half-balls has been examined using micromagnetic simulations and finite element methods. The comparison between disturbed and nondisturbed sample shapes enabled observations of the nature of switching, types of oscillations, and times of reversal, triggered by an externally applied magnetic field.
Correlation between primary phases and atomic clusters in a Zr-based metallic glass
Authors: Liu X. J. , Chen G. L. , Liu C. T.
Published: December 2010

Atomic clusters exiting in the Zr65Ti10Ni25 metallic glass and primary phases generated during crystallization were studied by x-ray scattering and high-resolution transmission microscopy. An intrinsic correlation between the atomic clusters and the primary phases has been revealed. It is found that there are topological icosahedral short-range orders (ISROs) in the as-cast sample in addition to fcc-Zr2Ni-type chemical SROs. These topological ISRO and fcc-Zr2Ni-type chemical SRO can simultaneously quasicrystallize/crystallize into the corresponding nanoscaled icosahedral quasicrystalline phase (I-phase) and fcc-Zr2Ni crystal as primary products during crystallization. The synchronic precipitation of these two metastable phases can be understood in terms of their structural similarity between the fcc-Zr2Ni and I-phase in local atomic configuration. In comparison with fcc-Zr2Ni crystal, the I-phase has a smaller size and lower volume fraction due to its lower growth rate attributed to its more complex composition and higher structural symmetry. The competitive growth between these two phases results in the development of nanostructured materials in this alloy after annealing.
Critical effect of dependency groups on the function of networks
Authors: Parshani Roni , Buldyrev Sergey V. , Havlin Shlomo
Published: December 2010

Current network models assume one type of links to define the relations between the network entities. However, many real networks can only be correctly described using two different types of relations. Connectivity links that enable the nodes to function cooperatively as a network and dependency links that bind the failure of one network element to the failure of other network elements. Here we present an analytical framework for studying the robustness of networks that include both connectivity and dependency links. We show that a synergy exists between the failure of connectivity and dependency links that leads to an iterative process of cascading failures that has a devastating effect on the network stability. We present exact analytical results for the dramatic change in the network behavior when introducing dependency links. For a high density of dependency links, the network disintegrates in a form of a first-order phase transition, whereas for a low density of dependency links, the network disintegrates in a second-order transition. Moreover, opposed to networks containing only connectivity links where a broader degree distribution results in a more robust network, when both types of links are present a broad degree distribution leads to higher vulnerability.
Transcription termination maintains chromosome integrity
Authors: Washburn Robert S. , Gottesman Max E.
Published: December 2010

DNA replication fork movement is impeded by collisions with transcription elongation complexes (TEC). We propose that a critical function of transcription termination factors is to prevent TEC from blocking DNA replication and inducing replication fork arrest, one consequence of which is DNA double-strand breaks. We show that inhibition of Rho-dependent transcription termination by bicyclomycin in
Escherichia coli
induced double-strand breaks. Cells deleted for Rho-cofactors
nusA
and
nusG
were hypersensitive to bicyclomycin, and had extensive chromosome fragmentation even in the absence of the drug. An RNA polymerase mutation that destabilizes TEC (
rpoB*35
) increased bicyclomycin resistance >40-fold. Double-strand break formation depended on DNA replication, and can be explained by replication fork collapse. Deleting recombination genes required for replication fork repair (
recB
and
ruvC
) increased sensitivity to bicyclomycin, as did loss of the replication fork reloading helicases
rep
and
priA
. We propose that Rho responds to a translocating replisome by releasing obstructing TEC.
Strain-resolved community genomic analysis of gut microbial colonization in a premature infant
Authors: Morowitz Michael J. , Denef Vincent J. , Costello Elizabeth K. , Thomas Brian C. , Poroyko Valeriy , Relman David A. , Banfield Jillian F.
Published: December 2010

The intestinal microbiome is a critical determinant of human health. Alterations in its composition have been correlated with chronic disorders, such as obesity and inflammatory bowel disease in adults, and may be associated with neonatal necrotizing enterocolitis in premature infants. Increasing evidence suggests that strain-level genomic variation may underpin distinct ecological trajectories within mixed populations, yet there have been few strain-resolved analyses of genotype–phenotype connections in the context of the human ecosystem. Here, we document strain-level genomic divergence during the first 3 wk of life within the fecal microbiota of an infant born at 28-wk gestation. We observed three compositional phases during colonization, and reconstructed and intensively curated population genomic datasets from the third phase. The relative abundance of two
Citrobacter
strains sharing ~99% nucleotide identity changed significantly over time within a community dominated by a nearly clonal
Serratia
population and harboring a lower abundance
Enterococcus
population and multiple plasmids and bacteriophage. Modeling of
Citrobacter
strain abundance suggests differences in growth rates and host colonization patterns. We identified genotypic variation potentially responsible for divergent strain ecologies, including hotspots of sequence variation in regulatory genes and intergenic regions, and in genes involved in transport, flagellar biosynthesis, substrate metabolism, and host colonization, as well as differences in the complements of these genes. Our results demonstrate that a community genomic approach can elucidate gut microbial colonization at the resolution required to discern medically relevant strain and species population dynamics, and hence improve our ability to diagnose and treat microbial community-mediated disorders.
Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F
Authors: Cencic Regina , Hall David R. , Robert Francis , Du Yuhong , Min Jaeki , Li Lian , Qui Min , Lewis Iestyn , Kurtkaya Serdar , Dingledine Ray , Fu Haian , Kozakov Dima , Vajda Sandor , Pelletier Jerry
Published: December 2010

Deregulation of cap-dependent translation is associated with cancer initiation and progression. The rate-limiting step of protein synthesis is the loading of ribosomes onto mRNA templates stimulated by the heterotrimeric complex, eukaryotic initiation factor (eIF)4F. This step represents an attractive target for anticancer drug discovery because it resides at the nexus of the TOR signaling pathway. We have undertaken an ultra-high-throughput screen to identify inhibitors that prevent assembly of the eIF4F complex. One of the identified compounds blocks interaction between two subunits of eIF4F. As a consequence, cap-dependent translation is inhibited. This compound can reverse tumor chemoresistance in a genetically engineered lymphoma mouse model by sensitizing cells to the proapoptotic action of DNA damage. Molecular modeling experiments provide insight into the mechanism of action of this small molecule inhibitor. Our experiments validate targeting the eIF4F complex as a strategy for cancer therapy to modulate chemosensitivity.
N-terminal domain of human Hsp90 triggers binding to the cochaperone p23
Authors: Karagöz G. Elif , Duarte Afonso M. S. , Ippel Hans , Uetrecht Charlotte , Sinnige Tessa , van Rosmalen Martijn , Hausmann Jens , Heck Albert J. R. , Boelens Rolf , Rüdiger Stefan G. D.
Published: December 2010

The molecular chaperone Hsp90 is a protein folding machine that is conserved from bacteria to man. Human, cytosolic Hsp90 is dedicated to folding of chiefly signal transduction components. The chaperoning mechanism of Hsp90 is controlled by ATP and various cochaperones, but is poorly understood and controversial. Here, we characterized the Apo and ATP states of the 170-kDa human Hsp90 full-length protein by NMR spectroscopy in solution, and we elucidated the mechanism of the inhibition of its ATPase by its cochaperone p23. We assigned isoleucine side chains of Hsp90 via specific isotope labeling of their δ-methyl groups, which allowed the NMR analysis of the full-length protein. We found that ATP caused exclusively local changes in Hsp90’s N-terminal nucleotide-binding domain. Native mass spectrometry showed that Hsp90 and p23 form a 2∶2 complex via a positively cooperative mechanism. Despite this stoichiometry, NMR data indicated that the complex was not fully symmetric. The p23-dependent NMR shifts mapped to both the lid and the adenine end of Hsp90’s ATP binding pocket, but also to large parts of the middle domain. Shifts distant from the p23 binding site reflect p23-induced conformational changes in Hsp90. Together, we conclude that it is Hsp90’s nucleotide-binding domain that triggers the formation of the Hsp90
2
p23
2
complex. We anticipate that our NMR approach has significant impact on future studies of full-length Hsp90 with cofactors and substrates, but also for the development of Hsp90 inhibiting anticancer drugs.
Spatial gradient of protein phosphorylation underlies replicative asymmetry in a bacterium
Authors: Chen Y. Erin , Tropini Carolina , Jonas Kristina , Tsokos Christos G. , Huang Kerwyn C. , Laub Michael T.
Published: December 2010

Spatial asymmetry is crucial to development. One mechanism for generating asymmetry involves the localized synthesis of a key regulatory protein that diffuses away from its source, forming a spatial gradient. Although gradients are prevalent in eukaryotes, at both the tissue and intracellular levels, it is unclear whether gradients of freely diffusible proteins can form within bacterial cells given their small size and the speed of diffusion. Here, we show that the bacterium
Caulobacter crescentus
generates a gradient of the active, phosphorylated form of the master regulator CtrA, which directly regulates DNA replication. Using a combination of mathematical modeling, single-cell microscopy, and genetic manipulation, we demonstrate that this gradient is produced by the polarly localized phosphorylation and dephosphorylation of CtrA. Our data indicate that cells robustly establish the asymmetric fates of daughter cells before cell division causes physical compartmentalization. More generally, our results demonstrate that uniform protein abundance may belie gradients and other sophisticated spatial patterns of protein activity in bacterial cells.
CompleteMOTIFs: DNA motif discovery platform for transcription factor binding experiments
Authors: Kuttippurathu Lakshmi , Hsing Michael , Liu Yongchao , Schmidt Bertil , Maskell Douglas L. , Lee Kyungjoon , He Aibin , Pu William T. , Kong Sek Won
Published: December 2010

Summary:CompleteMOTIFs (cMOTIFs) is an integrated web tool developed to facilitate systematic discovery of overrepresented transcription factor binding motifs from high-throughput chromatin immunoprecipitation experiments. Comprehensive annotations and Boolean logic operations on multiple peak locations enable users to focus on genomic regions of interest for de novo motif discovery using tools such as MEME, Weeder and ChIPMunk. The pipeline incorporates a scanning tool for known motifs from TRANSFAC and JASPAR databases, and performs an enrichment test using local or precalculated background models that significantly improve the motif scanning result. Furthermore, using the cMOTIFs pipeline, we demonstrated that multiple transcription factors could cooperatively bind to the upstream of important stem cell differentiation regulators.

Availability:  http://cmotifs.tchlab.org

Contact:  sekwon.kong@childrens.harvard.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Management of Urinary Incontinence in Primary Care
Authors: Rainsbury Paul G. , Fabricius Michael , McLarty Esther
Published: December 2010

Urinary incontinence (UI) is a common and important problem, which impacts on the physical, psychological and social well-being of sufferers as well as their families and carers. Most patients with UI can be assessed and managed by GPs without the need for referral to secondary care.
Common Oral Problems and Benign Lesions
Authors: Field Anne , Field Jennifer
Published: December 2010

There are a number of common oral problems (COPs) that patients may consult their GP about. Some patients are concerned about the appearance of structures within their mouth that are manifestations or variants of normal anatomical structures and only require reassurance. The majority of oral mucosal conditions are benign and do not represent any sinister pathology or an underlying systemic condition. This article describes the clinical presentation of some common oral lesions and conditions. Guidance is given concerning their management and when referral to an oral specialist is required. Recurrent mouth ulcers are the subject of another article in this journal.
An Empirical Bayes Approach to Estimating Ordinal Treatment Effects
Authors: Alvarez R. Michael , Bailey Delia , Katz Jonathan N.
Published: December 2010

Ordinal variables—categorical variables with a defined order to the categories, but without equal spacing between them—are frequently used in social science applications. Although a good deal of research exists on the proper modeling of ordinal response variables, there is not a clear directive as to how to model ordinal treatment variables. The usual approaches found in the literature for using ordinal treatment variables are either to use fully unconstrained, though additive, ordinal group indicators or to use a numeric predictor constrained to be continuous. Generalized additive models are a useful exception to these assumptions. In contrast to the generalized additive modeling approach, we propose the use of a Bayesian shrinkage estimator to model ordinal treatment variables. The estimator we discuss in this paper allows the model to contain both individual group—level indicators and a continuous predictor. In contrast to traditionally used shrinkage models that pull the data toward a common mean, we use a linear model as the basis. Thus, each individual effect can be arbitrary, but the model “shrinks” the estimates toward a linear ordinal framework according to the data. We demonstrate the estimator on two political science examples: the impact of voter identification requirements on turnout and the impact of the frequency of religious service attendance on the liberality of abortion attitudes.
The Luoping biota: exceptional preservation, and new evidence on the Triassic recovery from end-Permian mass extinction
Authors: Hu Shi-xue , Zhang Qi-yue , Chen Zhong-Qiang , Zhou Chang-yong , Lü Tao , Xie Tao , Wen Wen , Huang Jin-yuan , Benton Michael J.
Published: December 2010

The timing and nature of biotic recovery from the devastating end-Permian mass extinction (252 Ma) are much debated. New studies in South China suggest that complex marine ecosystems did not become re-established until the middle–late Anisian (Middle Triassic), much later than had been proposed by some. The recently discovered exceptionally preserved Luoping biota from the Anisian Stage of the Middle Triassic, Yunnan Province and southwest China shows this final stage of community assembly on the continental shelf. The fossil assemblage is a mixture of marine animals, including abundant lightly sclerotized arthropods, associated with fishes, marine reptiles, bivalves, gastropods, belemnoids, ammonoids, echinoderms, brachiopods, conodonts and foraminifers, as well as plants and rare arthropods from nearby land. In some ways, the Luoping biota rebuilt the framework of the pre-extinction latest Permian marine ecosystem, but it differed too in profound ways. New trophic levels were introduced, most notably among top predators in the form of the diverse marine reptiles that had no evident analogues in the Late Permian. The Luoping biota is one of the most diverse Triassic marine fossil Lagerstätten in the world, providing a new and early window on recovery and radiation of Triassic marine ecosystems some 10 Myr after the end-Permian mass extinction.
Detection of Candida albicans DNA from blood samples using a novel electrochemical assay
Authors: Muir Alastair , Forrest Gordon , Clarkson John , Wheals Alan
Published: December 2010

The genus Candida contains a number of yeast species which are opportunistic pathogens and are associated with life-threatening infections in immunocompromised individuals. Provision of appropriate therapy relies on the rapid identification of the infecting species, and existing methods of identifying Candida species in clinical samples are time and resource intensive and are not always specific enough to differentiate between drug-susceptible and drug-resistant species. We have previously developed a system for the rapid detection of yeast pathogens in clinical samples using PCR followed by hybridization with a suite of five species-specific, electrochemically labelled DNA probes. The limit of detection of the assay was shown to be 37 fg (∼1 genome) per reaction using extracted genomic DNA. We carried out a study to test the limit of detection of one of the probes, CA PR3, using blood samples from a healthy donor that were spiked with genomic DNA or with C. albicans cells. Our results demonstrated a limit of detection of 37 fg (ml blood)−1 (∼1 genome ml−1) using extracted DNA or 10 c.f.u. (ml blood)−1 using C. albicans cells, indicating that the assay is capable of detecting C. albicans nucleic acid at levels that are encountered in clinical samples.
Detection and species identification of microsporidial infections using SYBR Green real-time PCR
Authors: Polley Spencer D. , Boadi Samuel , Watson Julie , Curry Alan , Chiodini Peter L.
Published: December 2010

Diagnosis of microsporidial infections is routinely performed by light microscopy, with unequivocal non-molecular species identification achievable only through electron microscopy. This study describes a single SYBR Green real-time PCR assay for the simultaneous detection and species identification of such infections. This assay was highly sensitive, routinely detecting infections containing 400 parasites (g stool sample)−1, whilst species identification was achieved by differential melt curves on a Corbett Life Science Rotor-Gene 3000. A modification of the QIAamp DNA tissue extraction protocol allowed the semi-automated extraction of DNA from stools for the routine diagnosis of microsporidial infection by real-time PCR. Of 168 stool samples routinely analysed for microsporidian spores, only five were positive by microscopy. By comparison, 17 were positive for microsporidial DNA by real-time analysis, comprising 14 Enterocytozoon bieneusi, one Encephalitozoon cuniculi and two separate Pleistophora species infections.
The Hydroxypyruvate-Reducing System in Arabidopsis: Multiple Enzymes for the Same End
Authors: Timm Stefan , Florian Alexandra , Jahnke Kathrin , Nunes-Nesi Adriano , Fernie Alisdair R. , Bauwe Hermann
Published: December 2010

Hydroxypyruvate (HP) is an intermediate of the photorespiratory pathway that originates in the oxygenase activity of the key enzyme of photosynthetic CO2 assimilation, Rubisco. In course of this high-throughput pathway, a peroxisomal transamination reaction converts serine to HP, most of which is subsequently reduced to glycerate by the NADH-dependent peroxisomal enzyme HP reductase (HPR1). In addition, a NADPH-dependent cytosolic HPR2 provides an efficient extraperoxisomal bypass. The combined deletion of these two enzymes, however, does not result in a fully lethal photorespiratory phenotype, indicating even more redundancy in the photorespiratory HP-into-glycerate conversion. Here, we report on a third enzyme, HPR3 (At1g12550), in Arabidopsis (Arabidopsis thaliana), which also reduces HP to glycerate and shows even more activity with glyoxylate, a more upstream intermediate of the photorespiratory cycle. The deletion of HPR3 by T-DNA insertion mutagenesis results in slightly altered leaf concentrations of the photorespiratory intermediates HP, glycerate, and glycine, indicating a disrupted photorespiratory flux, but not in visible alteration of the phenotype. On the other hand, the combined deletion of HPR1, HPR2, and HPR3 causes increased growth retardation, decreased photochemical efficiency, and reduced oxygen-dependent gas exchange in comparison with the hpr1xhpr2 double mutant. Since in silico analysis and proteomic studies from other groups indicate targeting of HPR3 to the chloroplast, this enzyme could provide a compensatory bypass for the reduction of HP and glyoxylate within this compartment.
The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes
Authors: Loomba R. , Rivera M. M. , McBurney R. , Park Y. , Haynes‐Williams V. , Rehermann B. , Alter H. J. , Herrine S. K. , Liang T. J. , Hoofnagle J. H. , Heller T.
Published: December 2010

Aliment Pharmacol Ther 2011; 33: 559–565

Background  Acute hepatitis C has variable modes of presentation and frequently results in chronic infection. Its optimal management has yet to be defined.

Aim  To establish natural history and complications of treatment of acute hepatitis C.

Methods  Data from all patients presenting with acute hepatitis C to the National Institutes of Health between 1994 and 2007 were reviewed.

Results  Twenty‐five patients were identified. Symptoms were reported by 80% and jaundice by 40%. Aminotransferase levels and hepatitis C virus (HCV) RNA levels fluctuated greatly; 18% of patients were intermittently negative for HCV RNA. Five patients recovered spontaneously whereas 20 developed chronicity or received interferon‐based therapy during the acute phase. Among 15 patients treated during the acute phase with peginterferon with or without ribavirin for 24 weeks, all became HCV RNA negative within 4–8 weeks, and all except two (HIV‐positive) achieved a sustained virological response. Side effects (particularly psychiatric) were common and limited treatment in 30%.

Conclusions  Among 25 patients with acute HCV infection, fluctuating illness was common and spontaneous recovery occurred in only 20%. Anti‐viral treatment with a 24‐week course of peginterferon and ribavirin was highly effective, but marked by frequent and severe side effects.
Application of the WHO fracture risk assessment tool (FRAX) to predict need for DEXA scanning and treatment in patients with inflammatory bowel disease at risk of osteoporosis
Authors: Goodhand J. R. , Kamperidis N. , Nguyen H. , Wahed M. , Rampton D. S.
Published: December 2010

Aliment Pharmacol Ther 2011; 33: 551–558

Background  Although patients with inflammatory bowel disease (IBD) are at increased risk of osteoporosis, low bone mineral density (BMD) alone confers only a modest increase in risk of fracture. The FRAX score, developed by the WHO, is a free web‐based clinical scale assessing the 10‐year fracture risk and need for lifestyle advice/reassurance, dual X‐ray absorptiometry (DEXA) scanning or preventive treatment.

Aim  To assess the accuracy of pre‐BMD FRAX scores in identifying at risk IBD patients needing BMD measurement (intermediate risk) and/or therapy (high risk).

Methods  We calculated FRAX scores retrospectively in 116 consecutive IBD out‐patients (81 Crohn’s disease, 35 ulcerative colitis), who were having DEXA scans in 2005–2009 because they were considered at risk of osteoporosis.

Results  On DEXA scans, 47% (38/81) and 12% (10/81) patients with Crohn’s disease were osteopaenic and osteoporotic, respectively; equivalent figures for patients with UC were 34% (12/35) and 14% (5/35). The clinical FRAX score alone, when compared with the FRAX score including the BMD result, had a sensitivity of 100% (95% CI: 70–100%), specificity of 40% (95% CI: 31–50%), positive predictive value of 16% (95% CI: 9–27%) and negative predictive value of 100% (95% CI: 90–100%) in identifying those patients needing BMD measurement (intermediate risk) or preventive therapy (high risk).

Conclusions  In patients with IBD perceived to be at risk of osteoporosis and/or osteopaenia, the clinical FRAX score alone can predict accurately the risk of osteoporotic fracture, and thereby reduce the need for DEXA scans and unnecessary anti‐osteoporosis treatment.
‘Diprifusor’ for general and day‐case surgery
Authors: Coates D.
Published: December 2010

Total intravenous anaesthesia may be most beneficial for day‐case surgery with regard to quality of recovery, lack of complications and the ability to sustain an efficient throughput of patients. However, the technique can be applied to all forms of surgery and, with a little practice, consistent results will be achieved. Computerised infusion pumps can be programmed to provide a target blood concentration that can be easily varied to alter the anaesthetic state. The commercially available ‘Diprifusor’, a target controlled infusion system for propofol, can facilitate the more widespread use of total intravenous techniques and allow their potential benefits to be applied and appreciated more widely. This review outlines some practical considerations that should enable a more confident approach to total intravenous techniques by anaesthetists who are unfamiliar with them.
Influence of analgesic supplementation on the target propofol concentrations for anaesthesia with ‘Diprifusor’ TCI
Authors: Servin F. S. , Marchand‐Maillet F. , Desmonts J. M.
Published: December 2010

Forty healthy patients undergoing orthopaedic surgery were randomly allocated to receive an initial blood propofol target concentration of either 4 μg.ml−1 or 6 μg.ml−1 for induction of anaesthesia with a ‘Diprifusor’ target controlled infusion system for propofol, and analgesic supplementation with either nitrous oxide 67% in oxygen or alfentanil 15–20 μg.kg−1.h−1. Anaesthesia was induced within 3 min in 80% and 95% of patients with propofol target concentrations of 4 μg.ml−1 and 6 μg.ml−1, respectively. The frequency of discomfort on infusion was similar for both target concentrations. During maintenance, supplementary doses of alfentanil were required to provide adequate surgical conditions in approximately half of the patients receiving nitrous oxide. There was no statistically significant difference between the target concentration [mean (SD)] of propofol for total intravenous anaesthesia [5.1 (2.0) μg.ml−1] compared with a technique using nitrous oxide [4.6 (1.2) μg.ml−1] supplemented as needed with small doses of alfentanil.
Pharmacokinetic concepts for TCI anaesthesia
Authors: Gepts E.
Published: December 2010

The development of new short‐acting anaesthetic drugs, improved drug assay techniques and the availability of reliable infusion systems opened the field of clinical pharmacokinetics and pharmacodynamics. The tri‐exponential drug concentration decay complicates the definition of therapeutic dosage regimens and prevents straightforward prediction of recovery from drug effects. The context‐sensitive half‐time, the time required for drug blood concentration to decrease to half its value, provides a useful comparative predictor of drug concentration decline after infusion. The effect‐site equilibration time contributes to the delay of drug effect and intensifies the disequilibrium between drug blood concentrations and obtained effect following incremental dosage. The rationale for drug infusion is reduction of fluctuating drug concentrations and drug effects. A variability similar to that observed with the use of inhalation agents, must be achieved by the choice of an appropriate pharmacokinetic model. The use of a target controlled infusion device, delivering proportional changes based on pharmacokinetic principles, allows titration of the concentration against clinical effect in individual patients.
Practical use of ‘Diprifusor’ systems
Authors: Engbers F.
Published: December 2010

This paper describes practical aspects relating to the safe use of target controlled infusion systems in anaesthesia. Consideration is given to the correct use of syringes and infusion lines for any target controlled infusion system. The importance of appropriate connections, minimising infusion line dead space and the avoidance of syphoning are emphasised. The first two commercially available infusion pumps to incorporate the ‘Diprifusor’ module for the administration of propofol by target controlled infusion are the Graseby 3500 (Graseby Medical Ltd) and the Vial Master TCI (Fresenius Vial SA, originally developed by Becton Dickinson). Particular features of these systems are discussed. Finally, the practical consequences of possible misuse of infusion systems incorporating pharmacokinetic models are considered.
Prospective analysis of the impact of VEGF‐A gene polymorphisms on the pharmacodynamics of bevacizumab‐based therapy in metastatic breast cancer patients
Authors: Etienne‐Grimaldi Marie‐Christine , Formento Patricia , Degeorges Armelle , Pierga Jean‐Yves , Delva Rémi , Pivot Xavier , Dalenc Florence , Espié Marc , Veyret Corinne , Formento Jean‐Louis , Francoual Mireille , Piutti Magali , de Crémoux Patricia , Milano Gérard
Published: December 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Functional polymorphisms on the VEGF‐A gene, known to be linked to cancer risk or to VEGF‐A plasma concentrations, have been identified. So far, limited knowledge has been published on the relationships between toxicity/efficacy of bevacizumab‐based therapy and VEGF‐A polymorphisms (tumoral DNA). We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab‐based treatment administered in metastatic breast cancer patients.

WHAT THIS STUDY ADDS

• Present data obtained from a prospective study suggest a role for VEGF‐A 936C > T polymorphism as a potential predictor of time to progression in breast cancer patients receiving bevacizumab‐containing therapy. Also, the VEGF‐A−634G > C polymorphism was linked to bevacizumab‐related toxicity.

AIMS To test prospectively the impact of VEGF‐A gene polymorphisms on the pharmacodynamics of bevacizumab‐chemotherapy in breast cancer patients.

METHODS As part of the single‐arm MO19391 trial, 137 women with locally recurrent or metastatic breast cancer receiving first‐line bevacizumab‐containing therapy were analysed. Patients received bevacizumab associated (76%) or not (24%) with taxane‐based chemotherapy. Clinical evaluation included clinical response, time to progression (TTP) and a toxicity score corresponding to the sum of each maximum observed toxicity grade (hypertension, haemorrhage, arterial and venous thrombo‐embolism). Functional VEGF‐A polymorphisms at position −2578 C > A, −1498 T > C, −1154 G > A, −634 G > C and 936 C > T were analysed by PCR‐RFLP (blood DNA).

RESULTS Overall response rate (complete response (CR) + partial response (PR)) was 61%. Median TTP was 11 months. None of the VEGF‐A polymorphisms was significantly linked to clinical response. Analysis of the 936C > T polymorphism revealed that the 96 patients homozygous for the 936C allele exhibited a marked tendency for a shorter TTP (median 9.7 months) than the 32 patients bearing the 936T allele (median 11.5 months, P= 0.022) of which 30 were CT and two were homozygous TT. Other polymorphisms did not influence TTP. VEGF‐A−634 G > C was significantly related to the toxicity score with 39%, 49% and 81% of patients with score >1 in GG, GC and CC patients, respectively (P= 0.01).

CONCLUSIONS The role for VEGF‐A 936C > T polymorphism as a potential marker of TTP in breast cancer patients receiving bevacizumab‐containing therapy concords with the known impact of VEGF‐A 936C > T polymorphism on VEGF‐A expression.
Cannabis‐related hospitalizations: unexpected serious events identified through hospital databases
Authors: Jouanjus Emilie , Leymarie Florence , Tubery Marie , Lapeyre‐Mestre Maryse
Published: December 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The general knowledge on cannabis toxicity has improved, but quantitative data are still lacking.

• Little is known about the somatic complications associated with cannabis exposure. Available data rest upon case reports and only a few studies have been conducted in this field.

• Psychiatric disorders related to cannabis exposure are somehow still controversial.

WHAT THIS STUDY ADDS

• Quantitative estimates are key to comprehending the risks of medical outcomes in cannabis users, in particular the somatic complications of use. Our study suggests that cannabis use has to be linked to serious health defects, particularly neurological and cardiovascular disorders.

• Our study gives estimates of the annual incidence of cannabis‐related hospitalizations.

• Our study should contribute to enhancing the medical management of cannabis using patients.

AIMS Cannabis is the most prevalent illicit drug used worldwide and can be responsible for serious health defects in users. However, the risk related to cannabis consumption is not well established. The present study aimed to assess cannabis‐related adverse events leading to hospitalization, and to estimate the corresponding annual risk for consumers.

METHODS Participants were patients admitted to the public hospitals in the Toulouse area (France) between January 2004 and December 2007 in relation to the use of cannabis. Reasons for admission and other occurring events were identified through hospital discharge summaries. We described all observed adverse events (AEs) and estimated their regional incidence on the basis of cannabis consumption data.

RESULTS We included 200 patients, and identified a total of 619 adverse events (AEs), one of which was lethal. Psychiatric disorders involved 57.7% of patients and accounted for 18.2% of AEs. Most frequent outcomes were central and peripheral nervous system disorders (15.8% of AEs), acute intoxication (12.1%), respiratory system disorders (11.1%) and cardiovascular disorders (9.5%). We estimated that in 2007 the incidence of cannabis‐related AEs in the Midi‐Pyrenees region ranged from 1.2 per 1000 regular cannabis users (95% confidence interval (CI) 0.7, 1.6) to 3.2 (95% CI 2.5, 3.9).

CONCLUSIONS Cannabis use is associated with complications, considered to be serious since they lead to hospitalization. Beyond the well‐known and widely investigated psychiatric events, serious cerebro and cardiovascular complications have been identified. These findings contribute to improve the knowledge of cannabis‐related adverse events.
Orange and apple juice greatly reduce the plasma concentrations of the OATP2B1 substrate aliskiren
Authors: Tapaninen Tuija , Neuvonen Pertti J. , Niemi Mikko
Published: December 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Aliskiren is an antihypertensive drug with a low oral bioavailability.

• Aliskiren is eliminated primarily unchanged into bile, and it is a substrate of the organic anion transporting polypeptide 2B1 (OATP2B1) influx transporter, the P‐glycoprotein efflux transporter and cytochrome P450 3A4.

• Flavonoids in orange and apple juice have been shown to inhibit OATP2B1in vitro.

WHAT THIS STUDY ADDS

• Orange juice and apple juice markedly reduce the plasma concentrations of aliskiren probably by inhibiting its OATP2B1‐mediated intestinal absorption.

• Concomitant intake of aliskiren with orange or apple juice is best avoided.

AIMThe aim of this study was to investigate the effects of orange juice and apple juice on the pharmacokinetics and pharmacodynamics of aliskiren.

METHODSIn a randomized crossover study, 12 healthy volunteers ingested 200 ml of orange juice, apple juice or water three times daily for 5 days. On day 3, they ingested a single 150‐mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h and plasma renin activity up to 24 h.

RESULTSOrange and apple juice reduced aliskiren peak plasma concentrations by 80% (95% CI 63%, 89%,P< 0.001) and 84% (95% CI 72%, 91%,P< 0.001), and the area under the plasma aliskiren concentration–time curve (AUC) by 62% (95% CI 47%, 72%,P< 0.001) and 63% (95% CI 46%, 74%,P< 0.001), respectively, but had no significant effect on its elimination half‐life or renal clearance. The decreases in aliskiren AUC by orange and apple juice correlated with aliskiren AUC during the water phase (r= 0.98,P< 0.001). Plasma renin activity was 87% and 67% higher at 24 h after aliskiren during the orange juice and apple juice phases, respectively, than during the water phase (P< 0.05).

CONCLUSIONSOrange juice and apple juice greatly reduce the plasma concentrations and renin‐inhibiting effect of aliskiren, probably by inhibiting its OATP2B1‐mediated influx in the small intestine. Concomitant intake of aliskiren with orange or apple juice is best avoided.
Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man
Authors: Coiro Vittorio , Volpi Riccardo , Casti Amos , Maffei Maria Ludovica , Stella Adriano , Volta Elio , Chiodera Paolo
Published: December 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Alprazolam (ALP), a benzodiazepine activating GABAergic receptors, is involved in ACTH secretion.

WHAT THIS STUDY ADDS

• This study demonstrates a partial opioid influence in the inhibitory effect of ALP on the release of ACTH/cortisol during physical exercise.

AIMS To establish the possible involvement of alprazolam (ALP) and/or opiates in the mechanism underlying the ACTH/cortisol response to physical exercise.

METHODS Tests were carried out under basal conditions (exercise control test), exercise plus ALP (50 µg at time −90 min), naloxone (10 mg at time 0) or ALP plus naloxone. Plasma ACTH and serum cortisol concentrations were evaluated in blood samples taken before, during and after the bicycle ergometer tests.

RESULTS ACTH and cortisol concentrations rose significantly after physical exercise. Maximum peak at time 15 min (P ≤ 0.01 vs. baseline) for ACTH and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol. In the presence of naloxone, the ACTH and cortisol responses were significantly increased (maximum peak at time 20 min, P ≤ 0.02 vs. control test for ACTH, and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol) whereas they were abolished by ALP. When ALP and naloxone were given together, the inhibitory effect of ALP was partial.

CONCLUSIONS These data demonstrate an inhibitory effect of ALP in the regulation of the ACTH/cortisol response to physical exercise in man and suggest that GABAergic receptor activating benzodiazepines and opioids interact in the neuroendocrine secretion of ACTH/cortisol.