bluuebunny/crossref_metadata_2025 huggingface dataset:
Twist-enhanced stretchability of graphene nanoribbons: a molecular dynamics study
Authors: Li Ying
Published: November 2010

Graphene nanoribbons (GNRs) have many applications in electronics due to their exceptional mechanical, electronic and thermal properties. In order to utilize GNRs for stretchable electronics, it is an important issue to enhance the stretchability of GNRs. In this work, we report that the stretchability of GNRs can be considerably strengthened by a small twist angle through molecular dynamics simulations. Compared with the tension simulation on untwisted GNRs, twist effect can help the C–C covalent bond go into large nonlinear deformation, when the twisted GNR is under tension. Therefore, the breaking strain of a twisted GNR can be 37.6% larger than that of an untwisted one at room temperature. At the same time, the stiffness of the twisted GNR could also be enhanced. Such results could be useful for further application of GNRs in stretchable electronics with multi-functionality.
A performance enhanced PSI-BLAST based on hybrid alignment
Authors: Li Yuheng , Chia Nicholas , Lauria Mario , Bundschuh Ralf
Published: November 2010

Motivation: Sequence alignment is one of the most popular tools of modern biology. NCBI's PSI-BLAST utilizes iterative model building in order to better detect distant homologs with greater sensitivity than non-iterative BLAST. However, PSI-BLAST's performance is limited by the fact that it relies on deterministic alignments. Using a semi-probabilistic alignment scheme such as Hybrid alignment should allow for better informed model building and improved identification of homologous sequences, particularly remote homologs.

Results: We have built a new version of the tool in which the Smith-Waterman alignment algorithm core is replaced by the hybrid alignment algorithm. The favorable statistical properties of the hybrid algorithm allow the introduction of position-specific gap penalties in Hybrid PSI-BLAST. This improves the position-specific modeling of protein families and results in an overall improvement of performance.

Availability: Source code is freely available for download at http://bioserv.mps.ohio-state.edu/HybridPSI, implemented in C and supported on linux.

Contact:  bundschuh@mps.ohio-state.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Bloodstream infection caused by Acinetobacter junii in a patient with acute lymphoblastic leukaemia after allogenic haematopoietic cell transplantation
Authors: Cayô Rodrigo , Yañez San Segundo Lucrecia , Pérez del Molino Bernal Inmaculada Concepción , García de la Fuente Celia , Bermúdez Rodríguez Maria Aranzazu , Calvo Jorge , Martínez-Martínez Luis
Published: November 2010

Acinetobacter junii is a rare human pathogen associated with bacteraemia in neonates and paediatric oncology patients. We present a case of A. junii causing bacteraemia in an adult transplant patient with leukaemia. The correct identification of Acinetobacter species can highlight the clinical significance of the different species of this genus.
Innate immunity in the male genital tract: Chlamydia trachomatis induces keratinocyte-derived chemokine production in prostate, seminal vesicle and epididymis/vas deferens primary cultures
Authors: Mackern-Oberti Juan Pablo , Maccioni Mariana , Breser Maria Laura , Eley Adrian , Miethke Thomas , Rivero Virginia E.
Published: November 2010

Chlamydia trachomatisis an intracellular pathogen that infects mucosal epithelial cells, causing persistent infections. Although chronic inflammation is a hallmark of chlamydial disease, the proinflammatory mechanisms involved are poorly understood. Little is known about how innate immunity in the male genital tract (MGT) responds toC. trachomatis.Toll-like receptors (TLRs) are a family of receptors of the innate immunity that recognize different pathogen-associated molecular patterns (PAMPs) present in bacteria, viruses, yeasts and parasites. The study of TLR expression in the MGT has been poorly investigated. The aim of this work was to investigate the keratinocyte-derived chemokine (KC) response of MGT primary cultures from C57BL/6 mice toC. trachomatisand different PAMPs. KC production by prostate, seminal vesicle and epididymis/vas deferens cell cultures was determined by ELISA in culture supernatants. TLR2, 3, 4 and 9 agonists induced the production of KC by all MGT primary cultures assayed. In addition, we analysed the host response againstC. trachomatisandChlamydia muridarum.Chlamydial LPS (cLPS) as well asC. trachomatisandC. muridaruminfection induced KC secretion by all MGT cell cultures analysed. Differences in KC levels were observed between cultures, suggesting specific sensitivity against pathogens among MGT tissues. Chemokine secretion was observed after stimulation of seminal vesicle cells with TLR agonists, cLPS andC. trachomatis. To our knowledge, this is the first report showing KC production by seminal vesicle cells after stimulation with TLR ligands,C. trachomatisorC. muridarumantigens. These results indicate that different receptors of the innate immunity are present in the MGT. Understanding specific immune responses, both innate and adaptive, against chlamydial infections, mounted in each tissue of the MGT, will be crucial to design new therapeutic approaches where innate and/or adaptive immunity would be targeted.
Real-time evaluation of an optimized real-time PCR assay versus Brilliance chromogenic MRSA agar for the detection of meticillin-resistant Staphylococcus aureus from clinical specimens
Authors: Danial J. , Noel M. , Templeton K. E. , Cameron F. , Mathewson F. , Smith M. , Cepeda J. A.
Published: November 2010

A total of 1204 meticillin-resistant Staphylococcus aureus (MRSA) screens (3340 individual swabs) were tested to evaluate a staphylococcal cassette chromosome mec (SCCmec) real-time PCR. In total, 148 (12.3 %) of the screens were MRSA-positive, where 146 (12.1 %) were MRSA-positive by the SCCmec real-time PCR assay. In contrast, 128 (10.6 %) screens were MRSA-positive by culture. One hundred and twenty-six (10.5 %) of the screens were positive by both culture and PCR. Twenty of the 1204 screens (1.66 %) were negative by culture but positive by PCR; these samples were sequenced. In 14 of the cases, a homology search confirmed the sequence as SCCmec, indicating that these samples could be considered true positives. Two of the 1204 (0.2 %) screens were positive by culture and negative by PCR. The mean turnaround time (TAT) for PCR-negative swabs was 6 h 12 min and for PCR-positive swabs was 6 h 48 min. In comparison, for culture-negative swabs the mean TAT was 29 h 30 min and for culture-positive swabs was 69 h. The cost per swab for routine culture was £0.41 (€0.48) and that of the real-time PCR assay was £2.35 (€2.75). This optimized, in-house, inexpensive, real-time PCR test maintained a very high sensitivity and specificity when evaluated under real-time laboratory conditions. The TAT of this real-time PCR assay was substantially lower than that of chromogenic culture. It was also maintained throughout the entire process, which can be taken as an indirect measure of test performance. This study showed that implementation of a molecular test can be achieved with limited resources in a standard microbiology laboratory.
Roles of flavonoids and the transcriptional regulator TtsI in the activation of the type III secretion system of Bradyrhizobium elkanii SEMIA587
Authors: Bolzan de Campos Samanta , Deakin William J. , Broughton William J. , Passaglia Luciane M. P.
Published: November 2010

Bradyrhizobium elkanii SEMIA587 is a symbiotic nitrogen-fixing bacterium of the group commonly called rhizobia, which induce nodule formation in legumes, and is widely used in Brazilian commercial inoculants of soybean. In response to flavonoid compounds released by plant roots, besides Nod factors, other molecular signals are secreted by rhizobia, such as proteins secreted by type III secretion systems (T3SSs). Rhizobial T3SSs are activated by the transcription regulator TtsI, which binds to sequences present in the promoter regions of T3SS genes via a conserved sequence called the tts box. To study the role of the T3SS of B. elkanii SEMIA587, ttsI was mutated. Protein secretion and flavonoid induction analysis, as well as nodulation tests, were performed with the wild-type and mutant strains. The results obtained showed that B. elkanii SEMIA587 secretes at least two proteins (NopA and NopL, known rhizobial T3SS substrates) after genistein induction, whilst supernatants of the ttsI mutant did not contain these Nops. Unusually for rhizobia, the promoter region of the B. elkanii SEMIA587 ttsI gene contains a tts box, which is responsive to flavonoid induction and to which TtsI can bind. Nodulation tests performed with three different leguminous plants showed that the B. elkanii SEMIA587 ttsI mutant displays host-dependent characteristics; in particular, nodulation of two soybean cultivars, Peking and EMBRAPA 48, was more efficient when TtsI of B. elkanii was functional.
Genomic features and insights into the biology of Mycoplasma fermentans
Authors: Rechnitzer Hagai , Brzuszkiewicz Elzbieta , Strittmatter Axel , Liesegang Heiko , Lysnyansky Inna , Daniel Rolf , Gottschalk Gerhard , Rottem Shlomo
Published: November 2010

We present the complete genomic sequence ofMycoplasma fermentans, an organism suggested to be associated with the pathogenesis of rheumatoid arthritis in humans. The genome is composed of 977 524 bp and has a mean G+C content of 26.95 mol%. There are 835 predicted protein-coding sequences and a mean coding density of 87.6 %. Functions have been assigned to 58.8 % of the predicted protein-coding sequences, while 18.4 % of the proteins are conserved hypothetical proteins and 22.8 % are hypothetical proteins. In addition, there are two complete rRNA operons and 36 tRNA coding sequences. The largest gene families are the ABC transporter family (42 members), and the functionally heterogeneous group of lipoproteins (28 members), which encode the characteristic prokaryotic cysteine ‘lipobox’. Protein secretion occurs through a pathway consisting of SecA, SecD, SecE, SecG, SecY and YidC. Some highly conserved eubacterial proteins, such as GroEL and GroES, are notably absent. The genes encoding DnaK-DnaJ-GrpE and Tig, forming the putative complex of chaperones, are intact, providing the only known control over protein folding. Eighteen nucleases and 17 proteases and peptidases were detected as well as three genes for the thioredoxin-thioreductase system. Overall, this study presents insights into the physiology ofM. fermentans, and provides several examples of the genetic basis of systems that might function as virulence factors in this organism.
The Xanthomonas axonopodis pv. citri flagellum is required for mature biofilm and canker development
Authors: Malamud Florencia , Torres Pablo S. , Roeschlin Roxana , Rigano Luciano A. , Enrique Ramón , Bonomi Hernán R. , Castagnaro Atilio P. , Marano María Rosa , Vojnov Adrián A.
Published: November 2010

Xanthomonas axonopodis pv. citri (Xac) is the causative agent of citrus canker. This bacterium develops a characteristic biofilm on both biotic and abiotic surfaces. To evaluate the participation of the single flagellum of Xac in biofilm formation, mutants in the fliC (flagellin) and the flgE (hook) genes were generated. Swimming motility, assessed on 0.25 % agar plates, was markedly reduced in fliC and flgE mutants. However, the fliC and flgE mutants exhibited a flagellar-independent surface translocation on 0.5 % agar plates. Mutation of either the rpfF or the rpfC gene, which both encode proteins involved in cell–cell signalling mediated by diffusible signal factor (DSF), led to a reduction in both flagellar-dependent and flagellar-independent surface translocation, indicating a regulatory role for DSF in both types of motility. Confocal laser scanning microscopy of biofilms produced in static culture demonstrated that the flagellum is also involved in the formation of mushroom-shaped structures and water channels, and in the dispersion of biofilms. The presence of the flagellum was required for mature biofilm development on lemon leaf surfaces. The absence of flagellin produced a slight reduction in Xac pathogenicity and this reduction was more severe when the complete flagellum structure was absent.
Direct observation ofB-site cation displacements in Pb-based complex perovskite relaxor oxides
Authors: Baba-Kishi K. Z.
Published: November 2010

Electron diffraction patterns recorded using a scanning transmission electron microscope (STEM) from PbMg1/3Nb2/3O3(PMN) crystallites and PbZn1/3Nb2/3O3(PZN) crystals show weak and systematic continuous diffuse streaking along the 〈110〉 directions. Detailed high-angle annular dark-field (HAADF) images recordedviaan aberration-corrected STEM show that theB-site cations in PMN and PZN undergo correlated and long-range displacements towards the Pb2+ions on the (110) planes. The planarB-site displacement measured from the centres of the octahedra is about 0.3–0.5 Å in PMN and about 0.20–0.4 Å in PZN. In the HAADF images of the PMN crystallites and PZN crystals studied, there is insufficient evidence for systematic long-range planar displacements of the Pb2+ions. The observed Pb2+ion displacements in PMN and PZN appear randomly distributed, mostly displaced along 〈110〉 towards theB-site columns. There is also evidence of possible stress-related distortion in certain unit cells of PMN. In the relaxors studied, two distinct types of displacements were observed: one is the long-range planarB-site spatial displacement on the (110) planes, correlated with the Pb2+ions, possibly resulting in the observed diffuse streaking; the other is short-range Pb2+ion displacement on the (110) planes. The observed displacement status indicates a mutual attraction between the Pb ions and theB-site cations in which theBsites undergo the largest spatial displacements towards the Pb ions along 〈110〉.
SINGLE: a program to control single-crystal diffractometers
Authors: Angel R. J. , Finger L. W.
Published: November 2010

SINGLE, a program that runs under Windows operating systems, can be used to control a variety of four-circle Eulerian-cradle single-crystal diffractometers including Huber instruments equipped with Huber motor controllers, the Stoe Stadi-4 and the Siemens P4. The software can be configured,viavariables set by the user, to operate any of these diffractometers with a variety of environmental devices including furnaces and diamond-anvil pressure cells. It is specifically designed to determine unit-cell parameters to a precision of 1 part in 30 000.
X-ray phase measurements as a probe of small structural changes in doped nonlinear optical crystals
Authors: Morelhão Sérgio L. , Remédios Claúdio M. R. , Freitas Raul O. , dos Santos Adenilson O.
Published: November 2010

X-ray multiple diffraction experiments with synchrotron radiation were carried out on pure and doped nonlinear optical crystals: NH4H2PO4and KH2PO4doped with Ni and Mn, respectively. Variations in the intensity profiles were observed from pure to doped samples, and these variations correlated with shifts in the structure factor phases, also known as triplet phases. This result demonstrates the potential of X-ray phase measurements to study doping in this type of single crystal. Different methodologies for probing structural changes were developed. Dynamical diffraction simulations and curve fitting procedures were also necessary for accurate phase determination. Structural changes causing the observed phase shifts are discussed.
MoleCoolQt– a molecule viewer for charge-density research
Authors: Hübschle Christian B. , Dittrich Birger
Published: November 2010

MoleCoolQtis a molecule viewer for charge-density research. Features include the visualization of local atomic coordinate systems in multipole refinements based on the Hansen and Coppens formalism as implemented, for example, in theXDsuite. Residual peaks and holes fromXDfftare translated so that they appear close to the nearest atom of the asymmetric unit. Critical points from a topological analysis of the charge density can also be visualized. As in the programMolIso, color-mapped isosurfaces can be generated with a simple interface. Apart from its visualization features the program interactively helps in assigning local atomic coordinate systems and local symmetry, which can be automatically detected and altered. Dummy atoms – as sometimes required for local atomic coordinate systems – are calculated on demand;XDsystem files are updated after changes. When using the invariom database, potential scattering factor assignment problems can be resolved by the use of an interactive dialog. The following file formats are supported:XD,MoPro,SHELX,GAUSSIAN(com, FChk, cube), CIF and PDB.MoleCoolQtis written in C++ using the Qt4 library, has a user-friendly graphical user interface, and is available for several flavors of Linux, Windows and MacOS.
High-throughput powder diffraction on beamline I11 at Diamond
Authors: Parker Julia E. , Thompson Stephen P. , Cobb Tom M. , Yuan Fajin , Potter Jonathan , Lennie Alistair R. , Alexander Sam , Tighe Christopher J. , Darr Jawwad A. , Cockcroft Jeremy C. , Tang Chiu C.
Published: November 2010

A new capability designed for high-throughput (HT) structural analysis using the synchrotron powder diffraction beamline (I11) at Diamond Light Source is reported. With a high-brightness X-ray beam, multi-analyser detectors and fast data-acquisition procedures, high-quality diffraction data can be collected at a speed of ∼15–30 min per powder pattern for good crystalline materials. Fast sample changing at a rate of a few seconds per specimen is achieved with a robotic arm and pre-loaded capillary specimens on a multi-tray carousel (200-sample capacity). Additional equipment, such as an automatic powder-loading machine and a pre-alignment jig for the sample capillaries, is available to reduce preparation time. For demonstration purposes, the first results presented here are those from standard reference powders of Si, TiO2and TiO2/Si mixtures, obtained by analysing the data using Le Bail (instrumental calibration) and Rietveld refinements (quantitative agreement within 1%). The HT hardware was then used to study the structural phase evolution of a library of 31 La4Ni3−xFexO10heterometallic ceramic powders in less than 1 d. The powders were generated from a single heat treatment (at 1348 K in air for 12 h) of nanoceramic oxide co-precipitate precursors, made using a newly developed HT synthesis robot. Crystallographic details (symmetry and lattice parameters) were obtained as a function of Fe concentration. The results revealed that this approach was able to produce a pure Ruddlesden–Popper-type phase with an iron content of up tox= 0.5, significantly higher than has been achieved previously using more conventional synthesis routes and thus demonstrating the power of using the HT approach.
Supercritical carbon dioxide behavior in porous silica aerogel
Authors: Ciccariello Salvino , Melnichenko Yuri B. , He Lilin
Published: November 2010

Analysis of the tails of the small-angle neutron scattering (SANS) intensities relevant to samples formed by porous silica and carbon dioxide at pressures ranging from 0 to 20 MPa and at temperatures of 308 and 353 K confirms that the CO2fluid must be treated as a two-phase system. The first of these phases is formed by the fluid closer to the silica wall than a suitable distance δ and the second by the fluid external to this shell. The sample scattering-length densities and shell thicknesses are determined by the Porod invariants and the oscillations observed in the Porod plots of the SANS intensities. The resulting matter densities of the shell regions (thickness 15–35 Å) are approximately equal, while those of the outer regions increase with pressure and become equal to the bulk CO2at the higher pressures only in the low-temperature case.
Sample-displacement correction for whole-pattern profile fitting of powder diffraction data collected in capillary geometry
Authors: Scarlett Nicola Vivienne Yorke , Rowles Matthew R. , Wallwork Kia S. , Madsen Ian C.
Published: November 2010

Recentin situexperimentation at the Australian Synchrotron resulted in the nucleation and crystallization of material on the walls of the capillary reaction vessels. This lining of the capillary walls, without filling the bulk of the capillary volume, produced an artefact in the diffraction data due to sample displacement across the capillary. In effect, the experiment was examining simultaneously two samples displaced by equal and opposite amounts from the diffractometer centre. This was exaggerated by the fact that large-diameter (1 mm) capillaries had been used in order to increase the total sample volume and hence maximize the amount of material formed and examined. The effect of this displacement was to shift the diffraction peaks simultaneously to both lower and higher angles than their `ideal' positions, causing peak splitting in many instances. A model has been developed which considers the sample as being effectively two flat plate samples, thus allowing for correction through the use of sample displacement. An additional problem resulted from the oriented growth of the material on the capillary walls, producing preferred orientation in the observed data. The correction model can also be extended to model such anisotropic peak splitting caused by this preferential orientation of the crystallites on the capillary wall.
Phase II study of erlotinib plus gemcitabine in Japanese patients with unresectable pancreatic cancer
Authors: Okusaka Takuji , Furuse Junji , Funakoshi Akihiro , Ioka Tatsuya , Yamao Kenji , Ohkawa Shinichi , Boku Narikazu , Komatsu Yoshito , Nakamori Shoji , Iguchi Haruo , Ito Tetsuhide , Nakagawa Kazuhiko , Nakachi Kohei
Published: November 2010

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two‐step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m2 (i.v. days 1, 8, 15) in a 28‐day cycle in the first step, and efficacy and safety in the second step. The primary end‐point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment‐related death occurred. While interstitial lung disease‐like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1‐year survival rate and median progression‐free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425–431)
Cellular prion protein promotes glucose uptake through the Fyn‐HIF‐2α‐Glut1 pathway to support colorectal cancer cell survival
Authors: Li Qing‐Quan , Sun Yan‐Ping , Ruan Can‐Ping , Xu Xin‐Yun , Ge Jun‐Hui , He Jin , Xu Zu‐De , Wang Qiang , Gao Wen‐Chao
Published: November 2010

Cellular prion protein (PrPc) is a glycosylphosphatidylinositol‐anchored membrane protein that has various physical functions, including protection against apoptotic and oxidative stress, cellular uptake of copper ions, transmembrane signaling, and adhesion to the extracellular matrix. In this study, we show that PrPc is highly expressed in colorectal adenocarcinomas. Transcriptome profiling of PrPc‐depleted DLD‐1 cells revealed downregulation of glucose transporter 1 (Glut1). PrPc is shown to be involved in regulating Glut1 expression through the Fyn‐HIF‐2α pathway. As Glut1 is the natural transporter of glucose and is required for the high glycolytic rate seen in colorectal tumors, silencing of PrPc reduced the proliferation and survival rate of colorectal cancer cells in vitro. In vivo, knockdown of PrPc by hydrodynamic injection with a cocktail of PrPc–shRNA‐encoding plasmids also inhibited tumorigenicity in a xenograft model in nude mice. In summary, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of glycolysis. Targeting PrPc will therefore be a promising strategy to overcome the growth and survival advantage in colorectal tumors. (Cancer Sci 2011; 102: 400–406)
Roles of intrinsic angiogenesis inhibitor, vasohibin, in cervical carcinomas
Authors: Yoshinaga Kousuke , Ito Kiyoshi , Moriya Takuya , Nagase Satoru , Takano Tadao , Niikura Hitoshi , Sasano Hironobu , Yaegashi Nobuo , Sato Yasufumi
Published: November 2010

The aim of the present study is to clarify the critical roles of vasohibin in cervical carcinomas. We investigated the expression ratios of vasohibin and vascular endothelial growth factor (VEGF) receptor‐2 on endothelium and microvessel density, lymphatic vessel density (LVD) by immunohistochemistry. Sixty‐one squamous cell carcinoma (SCC), 18 mucinous adenocarcinoma (Adenocarcinoma), 38 carcinoma in situ (CIS), and 35 normal cervical epithelium were collected. We investigated the expression of vasohibin and compared it with the expression of VEGF receptor‐2 (VEGFR‐2, KDR/flk‐1), and CD34 in the stromal endothelium. Expression of VEGF was counted using the histological score (H score). D2‐40 was used as a marker for lymphatic endothelial cells to investigate LVD. The microvessel density of the normal cervical epithelium was significantly lower than that of CIS, SCC, and Adenocarcinoma (P < 0.05). The expression ratio of vasohibin in the normal cervical epithelium was significantly lower than that of SCC and Adenocarcinoma (P < 0.05). The expression ratio of VEGFR‐2 of the normal cervical epithelium was significantly lower than that of SCC and Adenocarcinoma (P < 0.05). The LVD of the normal cervical epithelium was significantly lower than that of CIS, SCC, and Adenocarcinoma (P < 0.05). For normal cervical epithelium, CIS, and SCC, there was a moderate correlation between the expression percentage of vasohibin and the expression percentage of VEGFR‐2 (P < 0.05, r2 = 0.3018). This is the first study to elucidate the correlation between the expression of vasohibin in the stromal endothelial cells and the expression of VEGFR‐2 in human cervical carcinomas. (Cancer Sci 2011; 102: 446–451)
Modification of recombinant maize ChitA chitinase by fungal chitinase‐modifying proteins
Authors: NAUMANN TODD A.
Published: November 2010

In commercial maize, there are at least two different alleles of the chiA gene that encode alloforms of ChitA chitinase, a protein that is abundant in developing seed. Both known alloforms are modified by Bz‐cmp, a chitinase‐modifying protein (cmp) secreted by the fungal pathogen Bipolaris zeicola. One alloform (ChitA‐B73) is also modified by Stm‐cmp, a protein secreted by the fungal pathogen Stenocarpella maydis, whereas the other (ChitA‐LH82) is resistant. The two ChitA alloforms possess six differences or polymorphisms (P1–P6). To determine whether the P2 polymorphism in the chitin‐binding domain is responsible for resistance or susceptibility to modification by Stm‐cmp, and to determine whether Stm‐cmp and Bz‐cmp are proteases, heterologous expression strains of the yeast Pichia pastoris that produce recombinant maize ChitA (rChitA) alloforms and mutant rChitAs were created. rChitA alloforms and mutant rChitAs were purified from yeast cultures and used as substrates in assays with Stm‐cmp and Bz‐cmp. As with native protein, Bz‐cmp modified both rChitA‐LH82 and rChitA‐B73, whereas Stm‐cmp modified rChitA‐B73 only. Mutant rChitAs, in which the P2 amino acids were changed to those of the other alloform, resulted in a significant exchange in Stm‐cmp susceptibility. Amino‐terminal sequencing of unmodified and modified rChitA‐B73 demonstrated that Stm‐cmp cleaves the peptide bond on the amino‐terminal side of the P2 alanine, whereas Bz‐cmp cleaves in the poly‐glycine hinge region, the site of P3. The results demonstrate that Stm‐cmp and Bz‐cmp are proteases that truncate ChitA chitinase at the amino terminus, but at different sites. Both sites correspond to polymorphisms in the two alloforms, suggesting that the sequence diversity at P2 and P3 is the result of selective pressure to prevent truncation by fungal proteases.
Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy
Authors: Adam de Beaumais Tiphaine , Fakhoury May , Medard Yves , Azougagh Said , Zhang Daolun , Yakouben Karima , Jacqz‐Aigrain Evelyne
Published: November 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacogenetic polymorphisms of both TPMT and ITPA are associated with individual variability in 6‐mercaptopurine (6‐MP) intracellular metabolism.

• The balance between red blood cell (RBC) 6‐thioguanine nucleotide (6TGN) and 6‐methylated metabolite (6‐MMPN) concentrations has an important impact on efficacy in children treated for acute lymphoblastic leukemia.

• Hepatotoxicity is a frequent complication of the association 6‐MP and methotrexate during maintenance therapy.

WHAT THIS STUDY ADDS

• RBC 6‐TGN concentrations are dependant on TPMT genotype and age, while RBC 6‐MMPN concentrations depend on TPMT and ITPA polymorphisms.

• Children aged 6 years or less had lower RBC 6‐TGN concentrations during maintenance therapy, demonstrating an age effect on 6‐MP intracellular metabolism.

• Hepatotoxicity is a frequent complication of the association of 6‐MP and methotrexate. A 6‐MMPN threshold of 5000 pmol/8 × 108RBC was associated with an increased risk of hepatotoxicity.

AIMS6‐mercaptopurine (6‐MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6‐thioguanine [6‐TGN] and 6‐methylmercaptopurine nucleotides [6‐MMPN]) are related to drug response. We investigated the impact of non‐genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6‐MP metabolism and response.

METHODSSixty‐six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most commonTPMTpolymorphisms, nine forITPA 94 C>Aand 17 forITPA IVS2+21 A>C. 6‐MP metabolites concentrations were analyzed by mixed model analysis.

RESULTSDuring maintenance, steady‐state RBC 6‐TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 108RBC) than in older children (600 pmol/8 × 108RBC). 6‐MMPN concentrations were low in patients withTPMTvariant/wild‐typeITPA(1862 pmol/8 × 108RBC), intermediate in wild‐type patients and high (16468 pmol/8 × 108RBC) in patients wild‐typeTPMT/variantITPA. A 6‐MMPN threshold of 5000 pmol/8 × 108RBC was associated with an increased risk of hepatotoxicity.

CONCLUSIONIn this study, age and bothTPMTandITPAgenotypes influenced 6‐MP metabolism. High 6‐MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.
Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?
Authors: Korstanje Cees , Krauwinkel Walter , van Doesum‐Wolters Francisca L. C.
Published: November 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The efficacy‐tolerability profile of tamsulosin in patients with benign prostatic hyperplasia (BPH) is assumed to be associated both with the α1‐adrenoceptor selectivity profile of the drug and a small peak : trough ratio in the plasma pharmacokinetic (PK) profile. Tamsulosin is highly bound to plasma proteins, notably α1‐acid glycoprotein (AGP). This protein is a high‐affinity binding protein and AGP plasma concentration was found to influence the therapeutic (unbound) plasma concentrations for high‐AGP‐binding drugs.

WHAT THIS STUDY ADDS

• The study actually assessed unbound tamsulosin concentrations in both blood plasma and prostate tissue and reported that the unbound tamsulosin concentrations after multiple dosing in men with BPH, were much higher in prostate than in blood plasma. The assumption is put forward that differential free drug concentrations in prostate and blood plasma may contribute to the relative ‘uroselectivity’ of tamsulosin.

AIMThe aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients.

METHODSForty‐one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6–21 days in order to reach steady‐state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (fu) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with14C‐tamsulosin.

RESULTSCmaxin plasma at 4.4 h for total tamsulosin was 15.2 ng ml−1and AUC(0,24 h) was 282 ng ml−1 h, while for prostateCmaxat 11.4 h post‐dose was 5.4 ng ml−1and AUC(0,24 h) was 120 ng ml−1 h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h).fuwas 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostatevs.plasmaCmaxconcentrations.

CONCLUSIONSThese data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma.
Cost‐effective age structure and geographical distribution of boreal forest reserves
Authors: Lundström Johanna , Öhman Karin , Perhans Karin , Rönnqvist Mikael , Gustafsson Lena
Published: November 2010

1. Forest reserves are established to preserve biodiversity, and to maintain natural functions and processes. Today there is heightened focus on old‐growth stages, with less attention given to early successional stages. The biodiversity potential of younger forests has been overlooked, and the cost‐effectiveness of incorporating different age classes in reserve networks has not yet been studied.

2. We performed a reserve selection analysis in boreal Sweden using the Swedish National Forest Inventory plots. Seventeen structural variables were used as biodiversity indicators, and the cost of protecting each plot as a reserve was assessed using the Heureka system. A goal programming approach was applied, which allowed inclusion of several objectives and avoided a situation in which common indicators affected the result more than rare ones. The model was limited either by budget or area.

3. All biodiversity indicators were found in all age classes, with more than half having the highest values in ages ≥ 100 years. Several large‐tree indicators and all deadwood indicators had higher values in forests 0–14 years than in forests 15–69 years.

4. It was most cost‐effective to protect a large proportion of young forests since they generally have a lower net present value compared to older forests, but still contain structures of importance for biodiversity. However, it was more area‐effective to protect a large proportion of old forests since they have a higher biodiversity potential per area.

5. The geographical distribution of reserves selected with the budget‐constrained model was strongly biassed towards the north‐western section of boreal Sweden, with a large proportion of young forest, whereas the area‐constrained model focussed on the south‐eastern section, with dominance by the oldest age class.

6. Synthesis and applications.We show that young forests with large amounts of structures important to biodiversity such as dead wood and remnant trees are cheap and cost‐efficient to protect. This suggests that reserve networks should incorporate sites with high habitat quality of different forest ages. Since young forests are generally neglected in conservation, our approach is of interest also to other forest biomes where biodiversity is adapted to disturbance regimes resulting in open, early successional stages.
Changes in quality of life in patients with breast cancer
Authors: Salonen Päivi , Kellokumpu‐Lehtinen Pirkko‐Liisa , Tarkka Marja‐Terttu , Koivisto Anna‐Maija , Kaunonen Marja
Published: November 2010

Aim.  To describe and compare changes in quality of life in two groups of patients with breast cancer and to identify factors predicting negative changes in quality of life within six months.

Background.  Women with breast cancer suffer from various treatment side‐effects, from psychological and social symptoms as well as decreased quality of life, creating a need for support that may persist throughout the breast cancer experience.

Design.  This six‐month longitudinal study involved a sample of 164 women, who were quasi‐randomized between intervention (n = 85) and control groups (n = 79) after breast cancer surgery. Intervention group received support and education via telephone one week after the breast cancer surgery and face‐to‐face support six months after the surgery. Quality of life was estimated one week and six months after breast cancer surgery, using the Quality of Life Index ‐ Cancer Version (QLI‐CV) and the European Organisation for Research and Treatment of Cancer Breast Cancer ‐ Specific Quality of Life questionnaire (EORTC QLQ‐BR23).

Method.  Data were analysed statistically using descriptive statistics and non‐parametric tests. Factors predicting negative changes in quality of life within six months were investigated using logistic regression models with the enter method.

Results.  Significant group difference in the magnitude of changes within six months was found in future outlook. Logistic regression analyses revealed six significant predictors of negative changes in quality of life within six months: education, employment status, having underaged children, chemotherapy, radiotherapy and hormonal therapy.

Conclusion.  The results of this study underline the importance of identifying quality of life changes in patients with breast cancer and paying attention to those women with difficulties in adapting to being a cancer survivor.

Relevance to clinical practice.  The findings of this study provide evidence which may help to create appropriate supportive interventions for both acute and long‐term settings.
Quality of life, anxiety and depression in ALS patients and their next of kin
Authors: Olsson Ozanne Anneli G , Strang Susann , Persson Lennart I
Published: November 2010

Aim and objectives.  The aims were to study health‐related quality of life, anxiety and depression in patients with amyotrophic lateral sclerosis and their next of kin and to compare these results with a subset of the general Swedish population. Thirty‐five pairs of patients with amyotrophic lateral sclerosis and their next of kin were studied.

Background.  Life changes in many ways when a person is diagnosed with amyotrophic lateral sclerosis. Comparison between patients, next of kin and the general population are needed to get a wider understanding of their quality of life, anxiety and depression.

Design.  A descriptive study.

Methods.  All participants were studied with the SF‐36 and the Hospital Anxiety and Depression Scale. Patients’ physical function was assessed by the amyotrophic lateral sclerosis Functional Rating Scale – Revised and the Norris scale.

Results.  A correlation was found in both the mental component summary in SF‐36 and in anxiety between the pairs of patients and their next of kin, while no correlation was found in the physical component summary or depression. These results were not related to the patients’ physical function. Both patients and their next of kin had some poorer ratings in SF‐36 and in anxiety and depression than the general Swedish population. Gender or age did not affect the estimates in any of the scales.

Conclusions.  The results indicate that both the patient and the next of kin are affected by the disease independent of physical disability. In most pairs of patient and next of kin, the mental component summary and anxiety were affected to a similar extent.

Relevance to clinical practice.  The results emphasise the need for medical and nursing support to both the patient and the next of kin soon after the diagnosis and during the course of the disease.
An outbreak of hepatitis B with high mortality in India: association with precore, basal core promoter mutants and improperly sterilized syringes
Authors: Arankalle V. A. , Gandhi S. , Lole K. S. , Chadha M. S. , Gupte G. M. , Lokhande M. U.
Published: November 2010

Summary.  In 2009, an outbreak of hepatitis B with high mortality was observed in Sabarkantha district, Gujarat state, India with 456 cases and 89 deaths. Hospitalized patients with self‐limiting disease (152, AVH)) and fulminant hepatic failure (39, FHF including 27 fatal and 12 survivals) were investigated. These were screened for diagnostic markers for hepatitis viruses, hepatitis B virus (HBV) genotyping and mutant analysis. Complete HBV genomes from 22 FHF and 17 AVH cases were sequenced. Serosurveys were carried out in the most and least affected blocks for the prevalence of HBV and identification of mutants. History of injection from a physician was associated with FHF and AVH cases. Co‐infection with other hepatitis viruses or higher HBV DNA load was not responsible for mortality. Four blocks contributed to 85.7% (391/456) of the cases and 95.5% (85/89) mortality while two adjacent blocks had negligible mortality. Sequence analysis showed the presence of pre‐core and basal core promoter mutants and 4 amino acid substitutions exclusively among FHF cases. None of the self‐limiting patients exhibited these dual mutations. Genotype D was predominant, D1 being present in all FHF cases while D2 was most prevalent in AVH cases. Probably due to violation of accepted infection control procedures by the qualified medical practitioners, HBV prevalence was higher in the affected blocks before the outbreak. Gross and continued use of HBV contaminated (mutant and wild viruses) injection devices led to an explosive outbreak with high mortality with a striking association with pre‐C/BCP mutants and D1 genotype.
Combined antiviral therapy of hepatitis C virus in dialysis patients: meta‐analysis of clinical trials
Authors: Fabrizi F. , Dixit V. , Martin P. , Messa P.
Published: November 2010

Summary.  The efficacy and safety of combined interferon (IFN) plus ribavirin in patients on long‐term dialysis and chronic hepatitis C remains unclear, although a number of small clinical trials have addressed this issue. We evaluated the efficacy and safety of combination antiviral therapy (conventional or pegylated interferon plus ribavirin) in dialysis patients with chronic hepatitis C by performing a systematic review of the literature with a meta‐analysis of clinical trials. The primary outcome was sustained virological response (SVR) (as a measure of efficacy); the secondary outcome was drop‐out rate (as a measure of tolerability). We used the random effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses. We identified 10 clinical studies (151 unique patients), one (10%) of which was a controlled clinical trial. Most (97.4%) patients were on long‐term haemodialysis. The summary estimate for SVR and drop‐out rate was 56% [95% Confidence Intervals (95% CI) 28–84] and 25% (95% CI, 10–40), respectively. The most frequent side effects requiring interruption of treatment were anaemia (26%) and heart failure (9%). These results occurred irrespective of type of interferon (conventional or peg‐IFN, peg‐IFNalfa‐2a or alfa‐2b), trial design (controlled or cohort study), or clinical characteristics of patients (naïve, nonresponders or relapsers). The studies were heterogeneous with regard to SVR and drop‐out rate. Combination antiviral therapy (interferon plus ribavirin) gives encouraging results in terms of efficacy and safety among dialysis patients even if the limited number of patients enrolled in our meta‐analysis hampers definitive conclusions.
Dutch elm disease revisited: past, present and future management in Great Britain
Authors: Harwood T. D. , Tomlinson I. , Potter C. A. , Knight J. D.
Published: November 2010

The arrival of a new species of the fungus which causes Dutch elm disease into Great Britain in the 1960s caused widespread elm death and continues to be problematic following elm regeneration. Attempts at managing the disease have been largely unsuccessful. Forty years after the outbreak, however, researchers continue to be interested in both the underlying biology of such a severe and dramatic disease event and in the policy lessons that can be drawn from it. We develop a spatial model at a 1 km2 resolution. Following parameterization to replay the historical epidemic, the model is used to explore previously proposed counterfactual management strategies. A new introduction date of late 1962 is estimated. We show that, even had there been high intervention at a national level in terms of disease management early in the epidemic, there would have been little long‐term effect on elm numbers. In Brighton, a local pocket of elm which survived the peak of the initial epidemic has been successfully managed. However, Brighton and similar locations are subject to repeated waves of the disease at a 15‐ to 20‐year intervals following regeneration and reinfection of the surrounding areas, during which much more intensive management is required.
Ciclosporin A therapy is associated with disturbances in glucose metabolism in dogs with atopic dermatitis
Authors: Kovalik Marcel , Thoday Keith L. , Handel Ian G. , de C. Bronsvoort Barend M. , Evans Helen , van den Broek Adri H. M. , Mellanby Richard J.
Published: November 2010

The effect of ciclosporin A (CsA) on glucose homeostasis was investigated in 16 dogs with atopic dermatitis by determining plasma glucose, serum fructosamine and insulin concentrations, and serial insulin and glucose concentrations following a glucagon stimulation test, before and 6 weeks after CsA therapy at 5 mg/kg once daily. All dogs completed the study. Following CsA treatment, the median serum fructosamine concentrations were significantly higher (pretreatment 227.5 μmol/L; post‐treatment 246.5 μmol/L; P = 0.001; reference range 162–310 μmol/L). Based on analyses of the areas under concentration‐time curves (AUC) pre‐ and post‐CsA treatment, plasma glucose concentrations were significantly higher (AUC without baseline correction 31.0 mmol/L/min greater; P = 0.021) and serum insulin concentrations were significantly lower (AUC without baseline correction 217.1 μIU/mL/min lower; P = 0.044) following CsA treatment. Peak glucose concentrations after glucagon stimulation test were significantly higher following CsA treatment (10.75 versus 12.05 mmol/L; P = 0.021), but there was no significant difference in peak serum insulin (52.0 versus 35.0 μIU/mL; P = 0.052). There was a negative correlation between baseline uncorrected insulin AUC and trough serum log CsA concentrations (r = −0.70, P = 0.005). The administration of CsA to dogs with atopic dermatitis leads to disturbances in glucose homeostasis. The clinical significance of this is unclear, but it should be taken into account when considering CsA treatment in dogs that already have such impairments.