bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of plant physiology and dynamic vegetation feedbacks in the climate response to low GHG concentrations typical of late stages of previous interglacials
Authors: Philippon‐Berthier Gwenaëlle , Vavrus Stephen J. , Kutzbach John E. , Ruddiman William F.
Published: April 2010

Using a version of NCAR's Community Climate System Model (CCSM3), we apply lowered greenhouse gas (GHG) concentrations (240 ppm CO2 and 450 ppb CH4) based on typical values reached during the latter stages of previous interglacials, which are not influenced by anthropogenic GHG emissions. Using these lowered GHG levels and including feedbacks both from vegetation changes produced by the dynamic vegetation model and from the plant physiological response to lowered CO2, the climate is 3.14 K cooler than in the modern control simulation. The plant physiology response alone is a small component of the total cooling globally (0.16 K), but it contributes an additional cooling of about half that caused by changes in vegetation distribution alone (0.29 K). The inclusion of plant physiology also amplifies the loss of high‐latitude boreal and tropical vegetation and enhances permanent snow cover area.
Imbalances in p97 co‐factor interactions in human proteinopathy
Authors: Fernández‐Sáiz Vanesa , Buchberger Alexander
Published: April 2010

The ubiquitin‐selective chaperone p97 is involved in major proteolytic pathways of eukaryotic cells and has been implicated in several human proteinopathies. Moreover, mutations in p97 cause the disorder inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD). The molecular basis underlying impaired degradation and pathological aggregation of ubiquitinated proteins in IBMPFD is unknown. Here, we identify perturbed co‐factor binding as a common defect of IBMPFD‐causing mutant p97. We show that IBMPFD mutations induce conformational changes in the p97 N domain, the main binding site for regulatory co‐factors. Consistently, mutant p97 proteins exhibit strongly altered co‐factor interactions. Specifically, binding of the ubiquitin ligase E4B is reduced, whereas binding of ataxin 3 is enhanced, thus resembling the accumulation of mutant ataxin 3 on p97 in spinocerebellar ataxia type 3. Our results suggest that imbalanced co‐factor binding to p97 is a key pathological feature of IBMPFD and potentially of other proteinopathies involving p97.
Probing high areal-density cryogenic deuterium-tritium implosions using downscattered neutron spectra measured by the magnetic recoil spectrometer
Authors: Frenje J. A. , Casey D. T. , Li C. K. , Séguin F. H. , Petrasso R. D. , Glebov V. Yu. , Radha P. B. , Sangster T. C. , Meyerhofer D. D. , Hatchett S. P. , Haan S. W. , Cerjan C. J. , Landen O. L. , Fletcher K. A. , Leeper R. J.
Published: April 2010

For the first time high areal-density (ρR) cryogenic deuterium-tritium (DT) implosions have been probed using downscattered neutron spectra measured with the magnetic recoil spectrometer (MRS) [J. A. Frenje et al., Rev. Sci. Instrum. 79, 10E502 (2008)], recently installed and commissioned on OMEGA [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)]. The ρR data obtained with the MRS have been essential for understanding how the fuel is assembled and for guiding the cryogenic program at the Laboratory for Laser Energetics (LLE) to ρR values up to ∼300 mg/cm2. The ρR data obtained from well-established charged particle spectrometry techniques [C. K. Li et al., Phys. Plasmas 8, 4902 (2001)] were used to authenticate the MRS data for low-ρR plastic capsule implosions, and the ρR values inferred from these techniques are in excellent agreement, indicating that the MRS technique provides high-fidelity data. Recent OMEGA-MRS data and Monte Carlo simulations have shown that the MRS on the NIF [G. H. Miller et al., Nucl. Fusion 44, S228 (2004)] will meet most of the absolute and relative requirements for determining ρR, ion temperature (Ti) and neutron yield (Yn) in both low-yield, tritium-rich, deuterium-lean, hydrogen-doped implosions and high-yield DT implosions.
Current control in ITER steady state plasmas with neutral beam steering
Authors: Budny R. V.
Published: April 2010

Predictions of quasisteady state DT plasmas in ITER [R. Aymar et al., Nucl. Fusion 41, 1301 (2001)] are generated using the PTRANSP code [R. V. Budny, Nucl. Fusion 49, 085008 (2009)]. The plasma temperatures, densities, boundary shape, and total current (9–10 MA) anticipated for ITER steady state plasmas are specified. Current drive by negative ion neutral beam injection, lower-hybrid, and electron cyclotron resonance are calculated. Four modes of operation with different combinations of current drive are studied. For each mode, scans with the negative ion neutral beam injection aimed at differing heights in the plasma are performed to study their effects on current control on the q profile. The time-evolution of the currents and q are calculated, and long-duration transients (up to ≃1500 s) are predicted. Effects of the beam and alpha ion pressures on the magnetohydrodynamic equilibrium are predicted to significantly alter the bootstrap current. The TEQ equilibrium solver [L. Degtyarev and V. Drozdov, Comput. Phys. Rep. 46, 481 (1985)] in PTRANSP is found to be much more accurate than the VMEC solver [S. P. Hirshman et al., J. Comput. Phys. 87, 396 (1990)]. Quasisteady state, strongly reversed q profiles are predicted for some beam injection angles when the current drive and bootstrap currents are sufficiently large.
The Couette configuration of the Los Alamos Neutron Science Center Neutron Rheometer for the investigation of polymers in the bulk via small-angle neutron scattering
Authors: Yearley Eric J. , Sasa Leslie A. , Welch Cynthia F. , Taylor Mark A. , Kupcho Kevin M. , Gilbertson Robert D. , Hjelm Rex P.
Published: April 2010

A neutron rheometer in the Couette geometry has been built at the Los Alamos Neutron Science Center to examine the molecular steady-state and dynamic responses of entangled polymeric materials in the bulk under the application of shear stress via small-angle neutron scattering. Although similar neutron rheometers have been fabricated elsewhere, this new design operates under the extreme conditions required for measuring the structure and behavior of high molecular weight polymer melts. Specifically, the rheometer achieves high torques (200 N m) and shear rates (865 s−1) simultaneously, never before attainable with other neutron rheometers at temperatures up to 240 °C under an inert gas environment. The design of the instrument is such that relatively small sample sizes are required. The testing of the Los Alamos Neutron Science Center Neutron Rheometer in the Couette design both as a rheometer and in the small-angle neutron optical configuration on highly viscous polystyrene is presented. The observed anisotropic neutron scattering pattern of the polystyrene melt at a molecular weight above entanglement provides evidence that the conformation of the polymer chains are elongated in the direction of the melt flow, in agreement with the current theories concerning linear polymers in the bulk.
An all solid-state, rolled strip pulse forming line with low impedance and compact structure
Authors: Yang Shi , Zhong Hui-Huang , Qian Bao-Liang , Yang Han-Wu
Published: April 2010

An all solid-state and compact pulsed strip pulse forming line (PFL) is investigated both theoretically and experimentally. The electromagnetic field distribution and the pulse formation in the strip PFL are analyzed numerically. Based on the theoretical analysis and numerical results, a rolled strip PFL with output voltage of 20 kV, pulse duration of 230 ns, and characteristic impedance of 0.5 Ω was designed and manufactured. We use the Mylar film and copper as the dielectric and conductor of the strip PFL. The dimension of the strip line is 23 000×400×1.6 mm3 in the case in which the strip line is unrolled, and the strip line is finally rolled into a cylinder of diameter of 311 mm for the experiment. The dimension and weight are about ten times smaller than those of traditional dielectric (oil or pure water) PFL with the same electrical parameters. Two experiments were performed using the strip line. One was for a transmission line experiment, and the other was for a PFL experiment. In the experiment of transmission line, the transmission time of the voltage signal was 115 ns, and the signal had almost no distortion, which verified the design. In the PFL experiment, results gave a 17.8 kV, 270 ns (full width at half maximum) voltage pulse which was a quasisquare wave on the water load of 0.5 Ω. The current going through the load is about 35.6 kA.
Ultrafast manipulation of hard x-rays by efficient Bragg switches
Authors: Herzog M. , Leitenberger W. , Shayduk R. , van der Veen R. M. , Milne C. J. , Johnson S. L. , Vrejoiu I. , Alexe M. , Hesse D. , Bargheer M.
Published: April 2010

We experimentally demonstrate efficient switching of the hard x-ray Bragg reflectivity of a SrRuO3/SrTiO3 superlattice by optical excitation of large-amplitude coherent acoustic superlattice phonons. The rocking curve changes drastically on a 1 ps timescale. The (0 0 116) reflection is almost extinguished (ΔR/R0=−0.91), while the (0 0 118) reflection increases by more than an order of magnitude (ΔR/R0=24.1). The change of the x-ray structure factor depends nonlinearly on the phonon amplitude, allowing manipulation of the x-ray response on a timescale considerably shorter than the phonon period. Numerical simulations for a superlattice with slightly changed geometry and realistic parameters predict a switching-contrast ratio ΔR/R0 of 700 with high reflectivity.
Effect of intrinsic surface stress on single-vertex structure of polarization in ferroelectric nanoparticles
Authors: Su Yu , Du Jing-Na
Published: April 2010

Intrinsic surface stress forms due to the relatively high surface energy of nanoscale ferroelectrics. Such surface stress induces mechanical balancing stress below the curved free surfaces, and consequently affects the existence of singe-vertex structure of polarization within free-standing ferroelectric nanostructures. A thermodynamics-based continuum phase field approach is employed to investigate such surface effect in ferroelectric nanodisks. It has been observed that, for a given material, the minimum geometric limit for existence of single-vertex structure will generally be elevated upon the compressive surface-induced stress. Such increase is nonlinear, and highly depending on the energy exchange parameter in the model.
Visualization of nitric oxide production in the mouse main olfactory bulb by a cell-trappable copper(II) fluorescent probe
Authors: McQuade Lindsey E. , Ma Jie , Lowe Graeme , Ghatpande Ambarish , Gelperin Alan , Lippard Stephen J.
Published: April 2010

We report the visualization of NO production using fluorescence in tissue slices of the mouse main olfactory bulb. This discovery was possible through the use of a novel, cell-trappable probe for intracellular nitric oxide detection based on a symmetric scaffold with two NO-reactive sites. Ester moieties installed onto the fluorescent probe are cleaved by intracellular esterases to yield the corresponding negatively charged, cell-impermeable acids. The trappable probe Cu
2
(FL2E) and the membrane-impermeable acid derivative Cu
2
(FL2A) respond rapidly and selectively to NO in buffers that simulate biological conditions, and application of Cu
2
(FL2E) leads to detection of endogenously produced NO in cell cultures and olfactory bulb brain slices.
Prolonged antigen survival and cytosolic export in cross-presenting human γδ T cells
Authors: Meuter Simone , Eberl Matthias , Moser Bernhard
Published: April 2010

Human blood Vγ9Vδ2 T cells respond to signals from microbes and tumors and subsequently differentiate into professional antigen-presenting cells (γδ T-APCs) for induction of CD4
+
and CD8
+
T cell responses. γδ T-APCs readily take up and degrade exogenous soluble protein for peptide loading on MHC I, in a process termed antigen cross-presentation. The mechanisms underlying antigen cross-presentation are ill-defined, most notably in human dendritic cells (DCs), and no study has addressed this process in γδ T-APCs. Here we show that intracellular protein degradation and endosomal acidification were significantly delayed in γδ T-APCs compared with human monocyte-derived DCs (moDCs). Such conditions are known to favor antigen cross-presentation. In both γδ T-APCs and moDCs, internalized antigen was transported across insulin-regulated aminopeptidase (IRAP)–positive early and late endosomes; however, and in contrast to various human DC subsets, γδ T-APCs efficiently translocated soluble antigen into the cytosol for processing via the cytosolic proteasome-dependent cross-presentation pathway. Of note, γδ T-APCs cross-presented influenza antigen derived from virus-infected cells and from free virus particles. The robust cross-presentation capability appears to be a hallmark of γδ T-APCs and underscores their potential application in cellular immunotherapy.
Pastor Iver Brink's Sacred and Secular Music: A Private Collection of Music from Copenhagen at the Beginning of the Eighteenth Century
Authors: Koudal Jens Henrik , Talbot Michael
Published: April 2010

Iver Brink (1665–1728) is familiar to students of Danish religious literature, but a published auction catalogue of his books (1729) shows him also to have been a discerning collector of music. Born in Norway, Brink settled in Copenhagen in 1686. After ordination, he became, in 1691, the first official pastor to the Danish community in London. Returning in 1701, he worked as pastor at two Copenhagen churches. In 1708–9 he accompanied King Frederik IV to Italy as chaplain. Brink's musical collection reflects his religious vocation, his travels to England, Italy and Germany, and especially his fondness for solo song of any description. He penned the texts of several devotional songs, and the ensemble music in his possession hints at his participation in social music-making. The breadth and connoisseurship displayed by his collection reinforces a growing perception that Danish musical culture in the early eighteenth century was less provincial than previously believed.
PepC: proteomics software for identifying differentially expressed proteins based on spectral counting
Authors: Heinecke N.L. , Pratt B.S. , Vaisar T. , Becker L.
Published: April 2010

Summary: Identifying biologically significant changes in protein abundance between two conditions is a key issue when analyzing proteomic data. One widely used approach centers on spectral counting, a label-free method that sums all the tandem mass spectra for a protein observed in an analysis. To assess the significance of the results, we recently combined the t-test and G-test, with random permutation analysis, and we validated this approach biochemically. To automate the statistical method, we developed PepC, a software program that balances the trade-off between the number of differentially expressed proteins identified and the false discovery rate. This tool can be applied to a wide range of proteomic datasets, making data analysis rapid, reproducible and easily interpretable by proteomics specialists and non-specialists alike.

Availability and implementation: The software is implemented in Java. It has been added to the Trans Proteomic Pipeline project's ‘Petunia’ web interface, but can also be run as a command line program. The source code is GNU Lesser General Public License and the program is freely available on the web. http://sashimi.svn.sourceforge.net/viewvc/sashimi/trunk/trans_proteomic_pipeline/src/Quantitation/Pepc

Contact:  levb@u.washington.edu; brian.pratt@insilicos.com
HangOut: generating clean PSI-BLAST profiles for domains with long insertions
Authors: Kim Bong-Hyun , Cong Qian , Grishin Nick V.
Published: April 2010

Summary: Profile-based similarity search is an essential step in structure-function studies of proteins. However, inclusion of non-homologous sequence segments into a profile causes its corruption and results in false positives. Profile corruption is common in multidomain proteins, and single domains with long insertions are a significant source of errors. We developed a procedure (HangOut) that, for a single domain with specified insertion position, cleans erroneously extended PSI-BLAST alignments to generate better profiles.

Availability: HangOut is implemented in Python 2.3 and runs on all Unix-compatible platforms. The source code is available under the GNU GPL license at http://prodata.swmed.edu/HangOut/

Contact:  kim@chop.swmed.edu; grishin@chop.swmed.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Exercise stroke volume and heart rate response differ in right and left heart failure
Authors: Groepenhoff Herman , Westerhof Nico , Jacobs Wouter , Boonstra Anco , Postmus Piet E. , Vonk‐Noordegraaf Anton
Published: April 2010

Aims

In pulmonary arterial hypertension (PAH), the exercise‐induced increase in stroke volume (SV) is limited by the increase in pulmonary artery pressure. In left heart failure (LHF), systemic arterial pressure increases little during exercise, and the SV increase is limited by the left ventricle itself. These differences might be reflected by a dissimilar SV and heart rate (HR) response to exercise, which could have important therapeutic implications, for example in beta‐blocker therapy. Therefore, we tested the hypothesis that SV and HR responses during exercise are different between PAH and LHF patients.

Methods and results

We included 28 PAH and 18 LHF patients (recruited from the heart failure unit) matched on a maximal oxygen uptake of <15 mL/kg/min, who were referred to our Pulmonary Function Department between 2000 and 2008 for a maximal cardio‐pulmonary exercise test. Only patients who had not been exposed to beta‐blockers were included. Pulmonary arterial hypertension and LHF patient groups had equally impaired exercise tolerance (about 42% of predicted) with a maximal oxygen uptake of 0.80 ± 0.29 and 0.86 ± 0.19 L/min. The peak SV response to exercise was significantly lower in PAH patients (−14 mL, P = 0.01); this was compensated by a steeper slope of HR relating to oxygen uptake (0.03 beats/mL, P = 0.001).

Conclusion

We conclude that PAH patients have a smaller SV response, but a larger HR response than LHF patients.
Candida tropicalis: its prevalence, pathogenicity and increasing resistance to fluconazole
Authors: Kothavade Rajendra J. , Kura M. M. , Valand Arvind G. , Panthaki M. H.
Published: April 2010

Candida tropicalishas been identified as the most prevalent pathogenic yeast species of theCandida-non-albicansgroup. Historically,Candida albicanshas been the major species responsible for causing candidiasis in immunocompromised and immunocompetent patients. However, infections (candidiasis) due toC. tropicalishave increased dramatically on a global scale thus proclaiming this organism to be an emerging pathogenic yeast. The reasons for this organism's dominance and its resistance to fluconazole have been difficult to elucidate. In addition, the mechanism of this organism's pathogenicity and the consequent immune response remain to be clarified. This paper describes certain predisposing factors potentially responsible for these characteristics and presents a ‘root cause analysis' to explain the increasing prevalence ofC. tropicalisin developed and undeveloped countries, as well as the organism's acquired drug resistance. Control measures against fluconazole resistance in clinical management have also been discussed.
Epidemiology of bacterial colonization at intensive care unit admission with emphasis on extended-spectrum β-lactamase- and metallo-β-lactamase-producing Gram-negative bacteria – an Indian experience
Authors: Azim Afzal , Dwivedi Mayank , Rao P. Bhaskar , Baronia A. K. , Singh R. K. , Prasad K. N. , Poddar Banani , Mishra Anshuman , Gurjar Mohan , Dhole T. N.
Published: April 2010

An important risk factor for nosocomial infection in an intensive care unit (ICU) is prior colonization. This study was undertaken to determine the spectrum of bacterial colonization and predisposing risk factors in patients being admitted to an ICU in India, with special emphasis on extended-spectrum β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing Gram-negative bacteria. Nasal, oral and rectal swab samples were collected and processed for isolation of ESBL-producing Gram-negative bacteria and MBL-producing Pseudomonas aeruginosa and Acinetobacter species. Bacterial colonization (of one or more sites) on admission was detected in 51 out of 96 patients included in the study. Non-fermenters, i.e. P. aeruginosa and Acinetobacter baumannii, were the most common colonizers, present in 37 patients, with simultaneous colonization in 12 patients. A total of 16 patients were colonized with MBL-producing members of the family Enterobacteriaceae, out of which 11 isolates (from 5 patients) were also carrying ESBL-encoding genes. As for MBLs, most of our patients have shown colonization with ESBL-producing bacteria. On admission, 47 of 51 patients (92 %) have been colonized by ESBL-producing members of the family Enterobacteriaceae, at one or more of the three anatomical sites. The most common MBL subtype was bla
IMP (51.56 %), whereas bla
CTX was the most common gene (84.9 %) identified among ESBL producers. Risk factors for colonization on admission to the ICU were hospitalization for more than 48 h, use of ≥3 groups of antibiotics, co-morbidities and mechanical ventilation for more than 48 h prior to ICU admission. There is an increasing incidence of MBLs and ESBLs in the Indian population. The identified risk factors can be used as a guide for empiric antibiotic therapy targeted to these resistant bacteria.
Intragenomic and intraspecific heterogeneity in rrs may surpass interspecific variability in a natural population of Veillonella
Authors: Michon Anne-Laure , Aujoulat Fabien , Roudière Laurent , Soulier Olivier , Zorgniotti Isabelle , Jumas-Bilak Estelle , Marchandin Hélène
Published: April 2010

As well as intraspecific heterogeneity, intragenomic heterogeneity between 16S rRNA gene copies has been described for a range of bacteria. Due to the wide use of 16S rRNA gene sequence analysis for taxonomy, identification and metagenomics, evaluating the extent of these heterogeneities in natural populations is an essential prerequisite. We investigated inter- and intragenomic 16S rRNA gene heterogeneity of the variable region V3 in a population of 149 clinical isolates of Veillonella spp. of human origin and in 13 type or reference Veillonella strains using PCR-temporal temperature gel electrophoresis (TTGE). 16S rRNA gene diversity was high in the studied population, as 45 different banding patterns were observed. Intragenomic heterogeneity was demonstrated for 110 (74 %) isolates and 8 (61.5 %) type or reference strains displaying two or three different gene copies. Polymorphic nucleotide positions accounted for 0.5–2.5 % of the sequence and were scattered in helices H16 and H17 of the rRNA molecule. Some of them changed the secondary structure of H17. Phylotaxonomic structure of the population based on the single-copy housekeeping gene rpoB was compared with TTGE patterns. The intragenomic V3 heterogeneity, as well as recombination events between strains or isolates of different rpoB clades, impaired the 16S rRNA-based identification for some Veillonella species. Such approaches should be conducted in other bacterial populations to optimize the interpretation of 16S rRNA gene sequences in taxonomy and/or diversity studies.
Single-cell measurement of the levels and distributions of the phosphorelay components in a population of sporulating Bacillus subtilis cells
Authors: Eswaramoorthy Prahathees , Dinh Jeffrey , Duan Daniel , Igoshin Oleg A. , Fujita Masaya
Published: April 2010

Upon nutrient starvation, the Gram-positive bacterium Bacillus subtilis switches from growth to sporulation by activating a multicomponent phosphorelay consisting of a major sensor histidine kinase (KinA), two phosphotransferases (Spo0F and Spo0B) and a response regulator (Spo0A). Although the primary sporulation signal(s) produced under starvation conditions is not known, it is believed that the reception of a signal(s) on the sensor kinase results in the activation of autophosphorylation of the enzyme. The phosphorylated kinase transfers the phosphate group to Spo0A via the phosphorelay and thus triggers sporulation. With a combination of quantitative immunoblot analysis, microscopy imaging and computational analysis, here we found that each of the phosphorelay components tested increased gradually over the period of sporulation, and that Spo0F was expressed in a more heterogeneous pattern than KinA and Spo0B in a sporulating cell population. We determined molecule numbers and concentrations of each phosphorelay component under physiological sporulation conditions at the single-cell level. Based on these results, we suggest that successful entry into the sporulation state is manifested by a certain critical level of each phosphorelay component, and thus that only a subpopulation achieves a sufficient intracellular quorum of the phosphorelay components to activate Spo0A and proceed successfully to the entry into sporulation.
Recruitment and growth of two small‐bodied resident fish species (Gobiidae and Atherinidae) in oligohaline, seasonally open lagoons
Authors: Close P. G. , Davies P. M. , Trayler K.
Published: April 2010

Spatio‐temporal recruitment patterns, growth and survival of the Swan River goby Pseudogobius olorum and western hardyhead Leptatherina wallacei are described from two small, coastal lagoons on the south coast of Western Australia. In these lagoons, estuarine salinity dynamics were relatively stable over much of the autumn–spring period when freshwater inputs from rivers were reduced and there was no oceanic connection. Preflexion and flexion stages of both fish species contributed strongly to population size structure in downstream reaches, whereas upstream reaches were dominated by postflexion larvae and juvenile stages. Spawning of both species was protracted and largely asynchronous, although the episodic presence of stronger preflexion and flexion cohorts suggested some synchronized spawning had occurred. Comparison with estuarine conditions over this period provided evidence that synchronized spawning may be related to temperature and salinity variations from a combination of freshwater inputs and periods of marine exchange. Uninterrupted growth and the progression of cohorts through to juvenile stages were consistent with the generally stable estuarine conditions. Larval and juvenile stages of both species were also tolerant of abrupt changes in salinity and temperature, which occurred due to a non‐seasonal oceanic connection. These findings were consistent with the euryhaline nature of adults of both species.
First record of the black bullhead Ameiurus melas (Teleostei: Ictaluridae) in Poland
Authors: Nowak M. , Koščo J. , Popek W. , Epler P.
Published: April 2010

The North American catfish, the black bullhead Ameiurus melas, is recorded for the first time in Poland. The origin of these fish is not clear, but their presence may be associated with unregulated introductions by anglers.
Influences of the environment on the endocrine and paracrine fish growth hormone–insulin‐like growth factor‐I system
Authors: Reinecke M.
Published: April 2010

Insulin‐like growth factor‐I (IGF‐I) is a key component of the complex system that regulates differentiation, development, growth and reproduction of fishes. The IGF‐I gene is mainly expressed in the liver that represents the principal source of endocrine IGF‐I but also in numerous other organs where the hormone most probably acts in an autocrine–paracrine manner. The primary stimulus for synthesis and release of IGF‐I is growth hormone (GH) from the anterior pituitary. Thus, in analogy to mammals, it is usual to speak of a fish ‘GH–IGF‐I axis'. The GH–IGF‐I system is affected by changes in the environment and probably represents a target of endocrine disrupting compounds (EDC) that impair many physiological processes in fishes. Thus, the review deals with the influences of changes in different environmental factors, such as food availability, temperature, photoperiod, season, salinity and EDCs, on GH gene expression in pituitary, IGF‐I gene expression in liver and extrahepatic sites and the physiological effects resulting from the evoked alterations in endocrine and local IGF‐I. Environmental influences certainly interact with each other but for convenience of the reader they will be dealt with in separate sections. Current trends in GH–IGF‐I research are analysed and future focuses are suggested at the end of the sections.
Lentiviral‐mediated miRNA against liver‐intestine cadherin suppresses tumor growth and invasiveness of human gastric cancer
Authors: Liu Qi‐Sheng , Zhang Jin , Liu Meng , Dong Wei‐Guo
Published: April 2010

Liver‐intestine cadherin (CDH17) represents a novel type of cadherin within the cadherin superfamily, and is distinguished from other cadherins by its distinct structural and functional features. Our previous studies had identified that increased CDH17 was significantly associated with tumor differentiation and lymph node metastasis in gastric cancer. In this study, we tested the hypothesis that CDH17 was associated with proliferation and invasiveness in gastric cancer using recombinant lentivirus‐mediated miRNA targeting to CDH17 both in vitro and in vivo. We also detected the activity of matrix metalloproteinase (MMP)‐2 and MMP‐9 with gelatin zymography to explore the mechanisms underlying the inhibition of the CDH17 gene. Our results showed that a well‐differentiated gastric cancer cell line had higher CDH17 expression. Down‐regulation of CDH17 inhibited proliferation, adherence, and invasion of the poorly differentiated BGC823 gastric cancer cells in vitro, and induced cell cycle arrest. The activities of MMP‐2 and MMP‐9 were lower in the CDH17‐miRNA‐transfected cells compared to the control cells. Using an in vivo tumor growth assay, we confirmed that CDH17 silencing could obviously slow the growth of gastric cancer derived from BGC823 cells. Taken together, we have demonstrated that CDH17 maybe a positive regulator for proliferative, adhesive, and invasive behaviors of gastric cancer. (Cancer Sci 2010)
The diagnosis and management of haemorrhoidal disease from a global perspective
Authors: ABRAMOWITZ L. , WEYANDT G. H. , HAVLICKOVA B. , MATSUDA Y. , DIDELOT J.‐M. , ROTHHAAR A. , SOBRADO C. , SZABADI A. , VITALYOS T. , WIESEL P.
Published: April 2010

Background  A treatment approach for patients with haemorrhoidal disease and other anal disease, which includes the use of topical corticosteroids and other topical combination products, is widely accepted, but little has been published to compare such treatments. This publication is a valuable collection of reading material for gastroenterologists, proctologists, general practitioners, dermatologists and other clinicians who are responsible for diagnosing and managing patients with haemorrhoidal disease.

Aims  To review and collect existing treatment approaches for haemorrhoidal disease, by reviewing global experience from clinicians that will contribute towards improving best practice in the management of patients.

Methods  The articles include overviews of haemorrhoidal disease, differential diagnosis, topical treatment and surgical practices and patient outcomes. Case studies further reinforce treatments from individual specialists.

Results  The articles between them address the classification of haemorrhoids, dermatological differential diagnoses of anal and perianal disease, and the therapeutic management of different haemorrhoidal diseases including invasive surgical and non‐invasive topical combination treatments. The case studies indicate the positive impact of appropriate treatment in everyday clinical practice.

Conclusion  This publication will reinforce best practice in the causative and symptomatic treatment of haemorrhoidal disease.

Aliment Pharmacol Ther 31 (Suppl. 1), 1–58
Body mass index, chronic atrophic gastritis and heartburn: a population‐based study among 8936 older adults from Germany
Authors: Gao L. , Weck M. N. , Rothenbacher D. , Brenner H.
Published: April 2010

Aliment Pharmacol Ther 2010; 32: 296–302

Background  Obesity and overweight have been positively related to gastro‐oesophageal reflux disease (GERD). It has been suggested that this relationship is as a consequence of an increased gastric acid reflux, which is caused by an enhanced intra‐abdominal pressure.

Aim  To assess potential interaction of the association between body mass index (BMI) and GERD by chronic atrophic gastritis, which goes along with decreased acid production.

Methods  In the baseline examination of ESTHER, a study conducted in 9953 older adults in Saarland, information on frequency of heartburn, potential risk factors and medical history was obtained by self‐administered standardized questionnaire. Serological measurements of pepsinogen I and II were taken for definition of chronic atrophic gastritis.

Results  In total, 2565 (28.7%) of the included subjects experienced heartburn within the previous 4 weeks. A pronounced dose‐response relationship was observed between BMI and heartburn occurrence (P < 0.001) among people without chronic atrophic gastritis, but not among people with chronic atrophic gastritis (P‐value for interaction = 0.018). Obese/overweight people with chronic atrophic gastritis had a much lower risk of heartburn compared with obese/overweight people without chronic atrophic gastritis (OR = 0.31, 95% CI = 0.24–0.40).

Conclusion  Our results are consistent with the hypothesis that BMI is related positively to GERD symptoms by its impact on acid reflux.
ORIGINAL ARTICLE: Autoimmunity predominates in a large South African cohort with addison’s disease of mainly European descent despite long‐standing disease and is associated with HLA DQB*0201
Authors: Ross Ian , Boulle Andrew , Soule Steven , Levitt Naomi , Pirie Fraser , Karlsson Anders , Mienie Japie , Yang Ping , Wang Hongjie , She Jin‐Xiong , Winter William , Schatz Desmond
Published: April 2010

Objective  We sought to determine whether autoimmunity is the predominant cause of Addison’s disease in South Africa and whether human leucocyte antigen (HLA) DQ association exists.

Design  We compiled a national registry of patients from primary care, referral centres and private practices.

Patients  A total of 144 patients, 94 of European descent, 34 Mixed Ancestry, 5 Asian and 11 Black Africans (mean age 45·9 years, range 2·7–88 years; mean duration of disease 13·1 years, range 0–50 years) and controls were matched for gender and ethnicity. All potential causes were investigated.

Results  Fifty one per cent of cases (74 patients) were autoimmune in aetiology. Either 21‐hydroxylase autoantibodies (72 patients, 50% of entire patient group) or adrenocortical autoantibodies (35 patients, 24%) were present, while 23% of patients had both. None of the Asian (n = 5) or Black (n = 11) patients had evidence of autoimmune disease. Overall 8% of patients had tuberculosis, 4% adrenoleucodystrophy, 1% adrenocorticotrophic hormone resistance syndrome and 6% X‐linked adrenal hypoplasia. In those with autoimmune disease primary hypothyroidism (47%), premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent accompanying autoimmune conditions. HLA DQB1*0201 alleles predominated in the autoimmune group (DQB1*0201: 65%vs 43% of controls P = 0·017) with the *0201/*0302 heterozygous genotype being the most prevalent (28%vs 8%P = 0·02).

Conclusions  While autoimmunity accounts for at least half of patients with Addison’s disease in South Africa and is associated with HLA DQB1*0201, none of the Black Africans or Asians in this cohort had adrenal autoantibodies. Moreover, 21‐hydroxylase autoantibodies were detectable in a higher proportion than adrenocortical autoantibodies, especially in those patients with a long history after disease onset.
Partial growth hormone deficiency in adults; should we be looking for it?
Authors: Shalet Stephen M.
Published: April 2010

Quantitatively, GH secretion exists as a continuum in states ranging from good health through to hypopituitarism. Currently, GH replacement is considered only for adults designated as being severely GH deficient (GHD). In clinical practice the gold standard, on which the biochemical diagnosis of severe GHD is based, centres on the presence of two or more additional anterior pituitary hormone deficits. Cohorts of adults with partial GHD (Growth Hormone Insufficiency [GHI]) have been reported with adverse body composition changes, dyslipidaemia, insulin resistance, altered cardiac performance and increased carotid intima‐media thickness. The diagnosis of GHI in an individual patient, however, is extremely difficult because such patients rarely exhibit additional anterior pituitary hormone deficits, and the levels of GH‐dependent proteins, including IGF‐I, are normal in the majority. Currently, GH replacement therapy should only be considered in a patient characterized as GHI by dynamic GH testing in whom there is a plausible cause for hypopituitarism and in whom the IGF‐I level is pathologically low.
ORIGINAL ARTICLE: Complications and death among elderly patients undergoing pituitary tumour surgery
Authors: Grossman Rachel , Mukherjee Debraj , Chaichana Kaisorn L. , Salvatori Roberto , Wand Gary , Brem Henry , Chang David C. , Quiñones‐Hinojosa Alfredo
Published: April 2010

Background  Preoperative determinants of surgical risk in elderly patients with pituitary tumour are not fully defined. The aim of this study was to quantify operative risk for these patients.

Design and methods  We performed a retrospective analysis of the Nationwide Inpatient Sample (1998–2005), a database containing discharge information from a stratified, random sample of 20% of all non‐federal hospitals in 37 states. Patients >65 years old who underwent pituitary tumour resection were identified by ICD‐9 coding. Primary outcome was inpatient death. Other outcomes included post‐operative complications, length of stay (LOS) and total charges.

Results  A total of 8400 patients (53·7% male) were identified. Mean age was 72·2. Mean co‐morbidity score was 5·3. A majority were white (82·0%) admitted to academic hospitals (69·5%) for elective procedures (55·7%). Inpatient mortality was 3·8%. The most common complication was fluid and electrolyte abnormalities (14·3%). Mean LOS was 8·5 days. In multivariate analysis, patients >80 years old had 30% greater odds of death, relative to 65–69 year old counterparts. Each complication increased LOS by an average of at least 4 days. These associations were statistically significant (P‐values <0·05).

Conclusions  New clinically relevant risk stratification information is now available to assist clinicians in operative decision‐making for elderly patients with pituitary tumour considering operative intervention.
Acoustic full waveform inversion of synthetic land and marine data in the Laplace domain
Authors: Ha Wansoo , Pyun Sukjoon , Yoo Jewoo , Shin Changsoo
Published: April 2010

Elastic waves, such as Rayleigh and mode‐converted waves, together with amplitude versus offset variations, serve as noise in full waveform inversion using the acoustic approximation. Heavy preprocessing must be applied to remove elastic effects to invert land or marine data using the acoustic inversion method in the time or frequency domains. Full waveform inversion using the elastic wave equation should be one alternative; however, multi‐parameter inversion is expensive and sensitive to the starting velocity model. We implement full acoustic waveform inversion of synthetic land and marine data in the Laplace domain with minimum preprocessing (i.e., muting) to remove elastic effects. The damping in the Laplace transform can be thought of as an automatic time windowing. Numerical examples show that Laplace‐domain acoustic inversion can yield correct smooth velocity models even with the noise originating from elastic waves. This offers the opportunity to develop an accurate smooth starting model for subsequent inversion in the frequency domain.
Modulation of factor VIII‐specific memory B cells
Authors: REIPERT B. M. , ALLACHER P. , HAUSL C. , PORDES A. G. , AHMAD R. U. , LANG I. , ILAS J. , WINDYGA J. , KLUKOWSKA A. , MUCHITSCH E. M. , SCHWARZ H. P.
Published: April 2010

Summary.  The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re‐exposure to the same antigen, they are rapidly re‐stimulated to proliferate and differentiate into antibody‐secreting plasma cells (ASC) that secrete high‐affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII‐specific memory B cells from becoming re‐stimulated. We established a 6‐day in vitro culture system that enabled us to study the regulation of FVIII‐specific murine memory‐B‐cell re‐stimulation. We tested the impact of the blockade of co‐stimulatory interactions, of different concentrations of FVIII and of ligands for toll‐like receptors (TLR). The blockade of B7‐CD28 and CD40‐CD40 ligand interactions prevented FVIII‐specific murine memory B cells from becoming re‐stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re‐stimulation of FVIII‐specific murine memory B cells. Triggering of TLR7 amplified re‐stimulation by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re‐stimulation of FVIII‐specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors.
Successful low dose immune tolerance induction in severe haemophilia A with inhibitors below 40 Bethesda Units
Authors: TER AVEST P. C. , FISCHER K. , GOUW S. C. , VAN DIJK K. , MAUSER‐BUNSCHOTEN E. P.
Published: April 2010

Summary.  Different regimens are used to achieve immune tolerance in patients with severe haemophilia A and inhibitory allo‐antibodies against factor VIII (FVIII). In this study, results of 26 years of low dose immune tolerance induction are evaluated. We evaluated 21 patients, who were treated with regular infusions of low dose FVIII (25–50 IU kg−1 every other day or three times a week) to obtain immune tolerance. Several risk factors for success rate and time to success were analysed. In 18 of 21 patients (86%) immune tolerance induction (ITI) was successful. The median of the maximum inhibitor titre before start of ITI was 4.5 BU mL−1. Success rate was associated with both a pre‐ITI titre and a maximum titre during ITI below 40 BU mL−1 (P = 0.003). The time to success was significantly shorter if the maximum inhibitor level during ITI was below 40 BU mL−1 (P = 0.040). In low titre inhibitors (<5 BU mL−1) this effect was even stronger (P = 0.033). Low dose immune tolerance induction therapy was successful in severe haemophilia A patients with a pre‐ITI titre below 40 BU mL−1. The time to success is predicted by a maximum ITI titre below 40 BU mL−1, and is even shorter in low titre inhibitors (<5 BU mL−1). We suggest that all patients with severe haemophilia A and a pre‐ITI inhibitor titre below 5 BU mL−1, should be treated with low dose immune tolerance induction therapy. Patients with a maximum titre below 40 BU mL−1 may also strongly benefit from the beneficial effects of low dose immune tolerance induction therapy.
Inhibitors in previously treated patients: a review of the literature
Authors: KEMPTON C. L.
Published: April 2010

Summary.  Previously treated patients are the first patients to receive novel factor VIII products during clinical investigations under the rationale that a product with increased antigenicity is more likely to be detected in this population because of a low baseline risk of inhibitor formation compared with previously untreated patients. As clinical investigations of factor products are not typically randomized comparisons, the rate of new inhibitor formation in a clinical trial is compared with the expected rates based on prior reports. The published experience of inhibitors in previously treated patients (PTPs) informs the number of new inhibitors per cohort that are acceptable in a clinical trial. However, a single acceptable limit of new inhibitors fails to recognize the heterogeneity of inhibitors and their variable impact on clinical care. This review will discuss the published literature on epidemiology and clinical characteristics of inhibitors and possible risk factors for formation in PTPs.
Gene therapy in haemophilia – going for cure?
Authors: MARGARITIS P. , HIGH K. A.
Published: April 2010

Summary.  Traditional treatment for haemophilia consists of bolus infusion of the missing coagulation factor, either prophylactically or on demand, but is complicated by the development of inhibitory antibodies to the infused factor. In those cases, as well as in patients with platelet defects or factor VII (FVII) deficiency, recombinant human activated FVII has been successfully used, but carries the disadvantage of a short plasma half‐life. As an alternative, emerging methodology based on gene transfer may be utilized to provide effective haemostasis in patients with coagulation defects. The goal of this article is to introduce the novel concept of continuous expression of activated FVII from a donated gene for the treatment of haemophilia, and to review the safety and efficacy data that have been produced so far by this approach in small and large animal models.
Health economics in haemophilia: a review from the clinician’s perspective
Authors: ESCOBAR M. A.
Published: April 2010

Summary. Health economic evaluations provide valuable information for healthcare providers, facilitating the treatment decision‐making process in a climate where demand for healthcare exceeds the supply. Although an uncommon disease, haemophilia is a life‐long condition that places a considerable burden on patients, healthcare systems and society. This burden is particularly large for patients with haemophilia with inhibitors, who can develop serious bleeding complications unresponsive to standard factor replacement therapies. Hence, bleeding episodes in these patients are treated with bypassing agents such as recombinant activated FVII (rFVIIa) and plasma‐derived activated prothrombin complex concentrates (pd‐APCC). With the efficacy of these agents now well established, a number of health economic studies have been conducted to compare their cost‐effectiveness for the on‐demand treatment of bleeding episodes in haemophiliacs with inhibitors. In a cost‐utility analysis, which assesses the effects of treatment on quality of life (QoL) and quantity of life, the incremental cost per quality‐adjusted life‐year (QALY) gained (US $44 834) indicated that rFVIIa was cost‐effective. Similarly, eight of 11 other economic modelling evaluations found that rFVIIa was more cost‐effective than pd‐APCC in the on‐demand treatment of bleeding episodes. These findings indicate that treating patients with haemophilia promptly and with the most effective therapy available may result in cost savings.
Management of difficult‐to‐treat inhibitor patients
Authors: GIANGRANDE P. L. F. , ESCOBAR M. A.
Published: April 2010

Summary. The workshop looked at seven scenarios based on fictional and real‐life cases of difficult‐to‐treat patients with haemophilia A or haemophilia B and inhibitors with the aim of sharing clinical opinion and experience from around the world. Delegate opinions on the best treatment option for each scenario are described together with actual treatment given in real‐life cases and its outcome.