bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep roots of upper plate faults and earthquake generation illuminated by volcanism
Authors: Ando Ryosuke , Okuyama Satoshi
Published: May 2010

For many years, the generation mechanism of disastrous intraplate earthquakes in the upper plate of a subduction zone have remained unclear largely because the roots of upper plate intraplate faults have particularly quiet inter‐seismic nature and limited visibility. Here we propose that the 2008 Mw 6.9 Iwate‐Miyagi Nairiku, Japan, Earthquake, occurred on a dipping fault in a volcanic region, contains previously‐unreported co‐seismic evidence of a ductile shear zone (DSZ) present on the down‐dip fault extension beneath the seismogenic layer, and DSZ plays a dominant role in the seismogenesis. We found the evidence in the spatial pattern of the co‐seismic ground displacement, which was well captured by synthetic aperture radar, reflecting geothermal anomalies there. A dynamic forward model including the inter‐seismic deformation of DSZ naturally reproduced this displacement pattern without kinematic inversions and consistently explained other independent observations. This finding should make breakthroughs in observational and theoretical studies of earthquake generation.
A slip pulse model with fault heterogeneity for low‐frequency earthquakes and tremor along plate interfaces
Authors: Ando Ryosuke , Nakata Ryoko , Hori Takane
Published: May 2010

Deep low‐frequency earthquakes (LFEs) and nonvolcanic tremor have distinctive characteristics unlike those of regular earthquakes, including strong anisotropy in their migration velocity and source spectra displaying 1/f decay. We show that a physical model can explain these features in a simple framework with slip pulses originating on fault heterogeneity and triggered by slow‐slip events. LFE/tremor source areas in the model consist of unstable patches sparsely and heterogeneously distributed following a Gaussian distribution. The difference in their migration speeds along dip and along strike was reproduced, without anisotropic rheological properties, by introducing alignments of their sources similar to observed streaks of LFEs/tremor. The key to reproducing inverse linear spectral decay is that the slip pulse has a constant mean moment rate. This model provides new insights into the physical source process of LFEs and tremor and should find practical use in assessing properties of deep plate interfaces.
Partitioned postseismic deformation associated with the 2009 Mw 6.3 L'Aquila earthquake surface rupture measured using a terrestrial laser scanner
Authors: Wilkinson M. , McCaffrey K. J. W. , Roberts G. , Cowie P. A. , Phillips R. J. , Michetti Alessandro Maria , Vittori E. , Guerrieri L. , Blumetti A. M. , Bubeck A. , Yates A. , Sileo G.
Published: May 2010

Using 3D terrestrial laser scan (TLS) technology, we have recorded postseismic deformation on and adjacent to the surface rupture formed during the 6th April 2009 L'Aquila normal faulting earthquake (Mw 6.3). Using surface modeling techniques and repeated surveys 8–124 days after the earthquake, we have produced a 4D dataset of postseismic deformation across a 3 × 65 m area at high horizontal spatial resolution. We detected millimetre‐scale movements partitioned between discrete surface rupture slip and development of a hangingwall syncline over 10's of meters. We interpret the results as the signal of shallow afterslip in the fault zone. We find 52% of the total postseismic hangingwall vertical motion occurs as deformation within 30 m of the surface rupture. The total postseismic vertical motions are approximately 50% that of the coseismic. We highlight the importance of quantifying partitioned postseismic contributions when applying empirical slip‐magnitude datasets to infer palaeoearthquake magnitudes.
Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways
Authors: Tchaparian Eskouhie , Marshal Lisa , Cutler Gene , Bauerly Kathryn , Chowanadisai Winyoo , Satre Michael , Harris Calliandra , Rucker Robert B.
Published: May 2010

PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ−) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ− rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ−/+) or partially depleted by feeding the PQQ− diet to PQQ+ rats for 48 h (PQQ+/−). RNA extracted from liver and a Codelink® UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ− diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P<0.01). PQQ repletion reversed the changes in transcript expression caused by PQQ deficiency and resulted in an alteration of 847 of the total transcripts examined (P<0.01). Genes important for cellular stress (e.g. thioredoxin), mitochondriogenesis, cell signalling [JAK (Janus kinase)/STAT (signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) pathways] and transport were most affected. qRT-PCR (quantitative real-time PCR) and functional assays aided in validating such processes as principal targets. Collectively, the results provide a mechanistic basis for previous functional observations associated with PQQ deficiency or PQQ administered in pharmacological amounts.
Functional characterization of leucine-specific domain 1 from eukaryal and archaeal leucyl-tRNA synthetases
Authors: Zhou Xiao-Long , Wang Meng , Tan Min , Huang Qian , Eriani Gilbert , Wang En-Duo
Published: May 2010

LeuRS (leucyl-tRNA synthetase) catalyses the esterification of tRNAsLeu with leucine. This family of enzymes is divided into prokaryotic and eukaryal/archaeal groups according to the presence and position of specific insertions and extensions. In the present study, we investigated the function of LSD1 (leucine-specific domain 1), which is naturally present in eukaryal/archaeal LeuRSs, but absent from prokaryotic LeuRSs. When mutated in their common domain, the eukaryal and archaeal LeuRSs exhibited defects in the first reaction step of amino acid activation with variations of leucine or ATP-binding strength, whereas the tRNA aminoacylation was moderately affected. When the eukaryal extension was mutated, severe tRNA charging defects were observed, suggesting that eukaryotes evolved this LSD1 extension in order to improve the aminoacylation reaction step. The results also showed that the LSD1s from organisms of both groups are dispensable for post-transfer editing. Together, the data provide us with a further understanding of the organization and structure of LeuRS domains.
NF-κB mediates lipid-induced fetuin-A expression in hepatocytes that impairs adipocyte function effecting insulin resistance
Authors: Dasgupta Suman , Bhattacharya Sushmita , Biswas Anindita , Majumdar Subeer S. , Mukhopadhyay Satinath , Ray Sukanta , Bhattacharya Samir
Published: May 2010

Fetuin-A, a hepatic secretory protein, has recently been implicated in insulin resistance and Type 2 diabetes. It is an endogenous inhibitor of insulin receptor tyrosine kinase. However, regulation of fetuin-A synthesis in relation to insulin resistance is unclear. In the present paper, we report that both non-esterified (‘free’) fatty acids and fetuin-A coexist at high levels in the serum of db/db mice, indicating an association between them. For an in-depth study, we incubated palmitate with HepG2 cells and rat primary hepatocytes, and found enhanced fetuin-A secretion to more than 4-fold over the control. Interestingly, cell lysates from these incubations showed overexpression and activity of NF-κB (nuclear factor κB). In NF-κB-knockout HepG2 cells, palmitate failed to increase fetuin-A secretion, whereas forced expression of NF-κB released fetuin-A massively in the absence of palmitate. Moreover, palmitate stimulated NF-κB binding to the fetuin-A promoter resulting in increased reporter activity. These results suggest NF-κB to be the mediator of the palmitate effect. Palmitate-induced robust expression of fetuin-A indicates the occurrence of additional targets, and we found that fetuin-A severely impaired adipocyte function leading to insulin resistance. Our results reveal a new dimension of lipid-induced insulin resistance and open another contemporary target for therapeutic intervention in Type 2 diabetes.
Organelle Biogenesis and Positioning in Plants
Authors: Evans David E. , Hawes Chris
Published: May 2010

The biogenesis and positioning of organelles involves complex interacting processes and precise control. Progress in our understanding is being made rapidly as advances in analysing the nuclear and organellar genome and proteome combine with developments in live-cell microscopy and manipulation at the subcellular level. This paper introduces the collected papers resulting from Organelle Biogenesis and Positioning in Plants, the 2009 Biochemical Society Annual Symposium. Including papers on the nuclear envelope and all major organelles, it considers current knowledge and progress towards unifying themes that will elucidate the mechanisms by which cells generate the correct complement of organelles and adapt and change it in response to environmental and developmental signals.
Targeting proteins to the plant nuclear envelope
Authors: Meier Iris , Zhou Xiao , Brkljacić Jelena , Rose Annkatrin , Zhao Qiao , Xu Xianfeng Morgan
Published: May 2010

The nuclear envelope and the nuclear pore are important structures that both separate and selectively connect the nucleoplasm and the cytoplasm. The requirements for specific targeting of proteins to the plant nuclear envelope and nuclear pore are poorly understood. How are transmembrane-domain proteins sorted to the nuclear envelope and nuclear pore membranes? What protein–protein interactions are involved in associating other proteins to the nuclear pore? Are there plant-specific aspects to these processes? We are using the case of the nuclear pore-associated Ran-cycle component RanGAP (Ran GTPase-activating protein) to address these fundamental questions. Plant RanGAP is targeted to the nuclear pore by a plant-specific mechanism involving two families of nuclear pore-associated proteins [WIP (WPP-domain-interacting protein) and WIT (WPP-domain-interacting tail-anchored protein)] not found outside the land plant lineage. One protein family (WIP or WIT) is sufficient for RanGAP targeting in differentiated root cells, whereas both families are necessary in meristematic cells. A C-terminal predicted transmembrane domain is sufficient for targeting WIP proteins to the nuclear envelope. Nuclear-envelope targeting of WIT proteins requires a coiled-coil domain and is facilitated by HSC70 (heat-shock cognate 70 stress protein) chaperones and a class of plant-specific proteins resembling the RanGAP-targeting domain (WPP proteins). Taken together, this sheds the first light on the requirements and interdependences of nuclear envelope and nuclear pore targeting in land plants.
Biogenesis of the plant Golgi apparatus
Authors: Hawes Chris , Schoberer Jennifer , Hummel Eric , Osterrieder Anne
Published: May 2010

It has long been assumed that the individual cisternal stacks that comprise the plant Golgi apparatus multiply by some kind of fission process. However, more recently, it has been demonstrated that the Golgi apparatus can be experimentally disassembled and the reformation process from the ER (endoplasmic reticulum) monitored sequentially using confocal fluorescence and electron microscopy. Some other evidence suggests that Golgi stacks may arise de novo in cells. In the present paper, we review some of the more recent findings on plant Golgi stack biogenesis and propose a new model for their growth de novo from ER exit sites.
Tonoplast intrinsic proteins and vacuolar identity
Authors: Gattolin Stefano , Sorieul Mathias , Frigerio Lorenzo
Published: May 2010

TIPs (tonoplast intrinsic proteins) have been traditionally used as markers for vacuolar identity in a variety of plant species and tissues. In the present article, we review recent attempts to compile a detailed map of TIP expression in Arabidopsis, in order to understand vacuolar identity and distribution in this model species. We discuss the general applicability of these findings. We also review the issue of the intracellular targeting of TIPs and propose key emerging questions relative to the cell biology of this protein family.
Plant dynamin-related protein families DRP1 and DRP2 in plant development
Authors: Bednarek Sebastian Y. , Backues Steven K.
Published: May 2010

Two separate families of Arabidopsis dynamin-related proteins, DRP1 and DRP2, have been implicated in clathrin-mediated endocytosis and cell plate maturation during cytokinesis. The present review summarizes the current genetic, biochemical and cell biological knowledge about these two protein families, and suggests key directions for more fully understanding their roles and untangling their function in membrane trafficking. We focus particularly on comparing and contrasting these two protein families, which have very distinct domain structures and are independently essential for Arabidopsis development, yet which have been implicated in very similar cellular processes during cytokinesis and cell expansion.
Peroxisome division and proliferation in plants
Authors: Aung Kyaw , Zhang Xinchun , Hu Jianping
Published: May 2010

Peroxisomes are eukaryotic organelles with crucial functions in development. Plant peroxisomes participate in various metabolic processes, some of which are co-operated by peroxisomes and other organelles, such as mitochondria and chloroplasts. Defining the complete picture of how these essential organelles divide and proliferate will be instrumental in understanding how the dynamics of peroxisome abundance contribute to changes in plant physiology and development. Research in Arabidopsis thaliana has identified several evolutionarily conserved major components of the peroxisome division machinery, including five isoforms of PEROXIN11 proteins (PEX11), two dynamin-related proteins (DRP3A and DRP3B) and two FISSION1 proteins (FIS1A/BIGYIN and FIS1B). Recent studies in our laboratory have also begun to uncover plant-specific factors. DRP5B is a dual-localized protein that is involved in the division of both chloroplasts and peroxisomes, representing an invention of the plant/algal lineage in organelle division. In addition, PMD1 (peroxisomal and mitochondrial division 1) is a plant-specific protein tail anchored to the outer surface of peroxisomes and mitochondria, mediating the division and/or positioning of these organelles. Lastly, light induces peroxisome proliferation in dark-grown Arabidopsis seedlings, at least in part, through activating the PEX11b gene. The far-red light receptor phyA (phytochrome A) and the transcription factor HYH (HY5 homologue) are key components in this signalling pathway. In summary, pathways for the division and proliferation of plant peroxisomes are composed of conserved and plant-specific factors. The sharing of division proteins by peroxisomes, mitochondria and chloroplasts is also suggesting possible co-ordination in the division of these metabolically associated plant organelles.
Relationships at the nuclear envelope: lamins and nuclear pore complexes in animals and plants
Authors: Fiserova Jindriska , Goldberg Martin W.
Published: May 2010

The nuclear envelope comprises a distinct compartment at the nuclear periphery that provides a platform for communication between the nucleus and cytoplasm. Signal transfer can proceed by multiple means. Primarily, this is by nucleocytoplasmic trafficking facilitated by NPCs (nuclear pore complexes). Recently, it has been indicated that signals can be transmitted from the cytoskeleton to the intranuclear structures via interlinking transmembrane proteins. In animal cells, the nuclear lamina tightly underlies the inner nuclear membrane and thus represents the protein structure located at the furthest boundary of the nucleus. It enables communication between the nucleus and the cytoplasm via its interactions with chromatin-binding proteins, transmembrane and membrane-associated proteins. Of particular interest is the interaction of the nuclear lamina with NPCs. As both structures fulfil essential roles in close proximity at the nuclear periphery, their interactions have a large impact on cellular processes resulting in affects on tissue differentiation and development. The present review concentrates on the structural and functional lamina–NPC relationship in animal cells and its potential implications to plants.
Motoring around the plant cell: insights from plant myosins
Authors: Sparkes Imogen A.
Published: May 2010

Organelle movement in plants cells is extremely dynamic. Movement is driven by the acto-myosin system. Higher plant myosins fall into two classes: classes XI and VIII. Localization studies have highlighted that myosins are present throughout the cytosol, label motile puncta and decorate the nuclear envelope and plasma membrane. Functional studies through expression of dominant-negative myosin variants, RNAi (RNA interference) and T-DNA insertional analysis have shown that class XI myosins are required for organelle movement. Intriguingly, organelle movement is also linked to Arabidopsis growth and development. The present review tackles current findings relating to plant organelle movement and the role of myosins.
Characterization and localization of dynein and myosins V and VI in the ovaries of queen bees
Authors: Patricio Karina , Calábria Karen Luciana , Peixoto Marco Pablo , Espindola Salmen Foued , Da Cruz‐Landim Carminda
Published: May 2010

The presence of myosin and dynein in the ovaries of both Apis mellifera and Scaptotrigona postica was investigated in extracts and in histological sections. In the ovary extracts, motor proteins, myosins V, VI and dynein were detected by Western blot. In histological sections, they were detected by immunocytochemistry, using a mouse monoclonal antibody against the intermediary chain of dynein and a rabbit polyclonal antibody against the myosin V head domain. The myosin VI tail domain was recognized by a pig polyclonal antibody. The results show that these molecular motors are expressed in the ovaries of both bee species with few differences in location and intensity, in regions where movement of substances is expected during oogenesis. The fact that antibodies against vertebrate proteins recognize proteins of bee species indicates that the specific epitopes are evolutionarily well preserved.
Inhibition of microRNA‐14 contributes to actinomycin‐D‐induced apoptosis in the Sf9 insect cell line
Authors: Kumarswamy Regalla , Chandna Sudhir
Published: May 2010

Actinomycin‐D (Act‐D) and other inhibitors of RNA synthesis induce extensive and rapid apoptosis in the lepidopteran insect cells. Interestingly, a similar effect is not observed in the case of protein synthesis shutdown, implying that certain RNA species may be critically required for cell survival. In order to assess whether depletion of certain anti‐apoptotic microRNAs may result in insect cell apoptosis induced by these transcriptional inhibitors, we inhibited two antiapoptotic microRNAs, viz. bantam and miR‐14 (microRNA‐14), with known functions in insect systems, by transfecting lepidopteran Sf9 cell line (derived from Spodoptera frugiperda) with sequence‐specific inhibitory anti‐miRs. Our results indicate that miR‐14 is indeed required for constitutive cell survival as its inhibition caused considerable apoptosis. Importantly, exogenous supplementation with the mimics of miR‐14 precursor molecules could partially inhibit the Act‐D‐induced Sf9 cell death. Further, our results indicate that miR‐14 may function downstream of mitochondrial cytochrome c release in preventing Act‐D‐induced apoptosis, implying possible inhibitory interactions with caspases as reported previously in other organisms. While the microRNA species are known to regulate cell death in Drosophila, which belongs the insect order Diptera, the present study demonstrates a definitive antiapoptotic role of miR‐14 in lepidopteran apoptosis as well. Our study also indicates that additional microRNA species may be regulating lepidopteran cell survival and death, thus warranting further in‐depth investigations into these important mechanisms of cell death. Since lepidopteran cells are an excellent model for general stress resistance, this study presents important information about their stress response mechanisms.
Secretion of the heat shock proteins HSP70 and HSC70 by baby hamster kidney (BHK‐21) cells
Authors: Evdokimovskaya Yulia , Skarga Yuri , Vrublevskaya Veronika , Morenkov Oleg
Published: May 2010

The HSPs (heat‐shock proteins) of the 70‐kDa family, the constitutively expressed HSC70 (cognate 70‐kDa heat‐shock protein) and the stress‐inducible HSP70 (stress‐inducible 70‐kDa heat‐shock protein), have been reported to be actively secreted by various cell types. The mechanisms of the release of these HSPs are obscure, since they possess no consensus secretory signal sequence. We showed that baby hamster kidney (BHK‐21) cells released HSP70 and HSC70 in a serum‐free medium and that this process was the result of an active secretion of HSPs rather than the non‐specific release of the proteins due to cell death. It was found that the secretion of HSP70 and HSC70 is independent of de novo protein synthesis. BFA (Brefeldin A) did not inhibit the basal secretion of HSPs, indicating that the secretion of HSP70 and HSC70 from cells occurs by a non‐classical pathway. Exosomes did not contribute to the secretion of HSP70 and HSC70 by cells. MBC (methyl‐β‐cyclodextrin), a substance that disrupts the lipid raft organization, considerably reduced the secretion of both HSPs, indicating that lipid rafts are involved in the secretion of HSP70 and HSC70 by BHK‐21 cells. The results suggest that HSP70 and HSC70 are actively secreted by BHK‐21 cells in a serum‐free medium through a non‐classical pathway in which lipid rafts play an important role.
Overexpression of STARD3 in human monocyte/macrophages induces an anti-atherogenic lipid phenotype
Authors: Borthwick Faye , Allen Anne-Marie , Taylor Janice M. , Graham Annette
Published: May 2010

Dysregulated macrophage cholesterol homoeostasis lies at the heart of early and developing atheroma, and removal of excess cholesterol from macrophage foam cells, by efficient transport mechanisms, is central to stabilization and regression of atherosclerotic lesions. The present study demonstrates that transient overexpression of STARD3 {START [StAR (steroidogenic acute regulatory protein)-related lipid transfer] domain 3; also known as MLN64 (metastatic lymph node 64)}, an endosomal cholesterol transporter and member of the ‘START’ family of lipid trafficking proteins, induces significant increases in macrophage ABCA1 (ATP-binding cassette transporter A1) mRNA and protein, enhances [3H]cholesterol efflux to apo (apolipoprotein) AI, and reduces biosynthesis of cholesterol, cholesteryl ester, fatty acids, triacylglycerol and phospholipids from [14C]acetate, compared with controls. Notably, overexpression of STARD3 prevents increases in cholesterol esterification in response to acetylated LDL (low-density lipoprotein), blocking cholesteryl ester deposition. Thus enhanced endosomal trafficking via STARD3 induces an anti-atherogenic macrophage lipid phenotype, positing a potentially therapeutic strategy.
Contrast-enhanced magnetic resonance angiography
Authors: Jonas Svensson
Published: May 2010

Svensson J. Contrast-Enhanced Magnetic Resonance Angiography. Development and optimization of techniques for paramagnetic and hyperpolarized contrast media. Stockholm 2001. ISBN 91-628-5322-8.

Contrast-enhanced magnetic resonance angiography (CE-MRA) is a diagnostic method for imaging of vascular structures based on nuclear magnetic resonance. Vascular enhancement is achieved by injection of a contrast medium (CM). Studies were performed using two different types of CM: conventional paramagnetic CM, and a new type ofCMbased on hyperpolarized (HP) nuclei.

The effects of varying CM concentration with time during image acquisition were studied by means of computer simulations using two different models. It was shown that a rapid concentration variation during encoding of the central parts of k-space could result in signal loss and severe image artifacts. The results were confirmed qualitatively with phantom experiments.

A postprocessing method was developed to address problems with simultaneous enhancement of arteries and veins in CE-MRA of the lower extremities. The method was based on the difference in flow-induced phase in the two vessel types. Evaluation of the method was performed with flow phantom measurements and with CE-MRA in two volunteers using standard pulse sequences.

The flow-induced phase in the vessels of interest was sufficient to distinguish arteries from veins in the superior-inferior direction. Using this method, the venous enhancement could be extinguished.

The possibility of using HP nuclei as CM for CE-MRA was evaluated. Signal expressions for a flow of HP CMimaged with a gradient echo sequence were derived. These signal expressions were confirmed in phantom experiments using HP 129Xe dissolved in ethanol.

Studies were also performed with a new CM based on HP 13C. The CM had very long relaxation times ( T1,in vivo/ T2,in vivo ≈ 38/1.3 s). The long relaxation times were utilized in imaging with a fully balanced steady-state free precession pulse sequence (trueFISP), where the optimal flip angle was found to be 180°. CE-MRA with the 13C-based CM in rats resulted in images with high vascular SNR (∼500).

CE-MRA is a useful clinical tool for diagnosing vascular disease. With the development of new contrast media, based on hyperpolarized nuclei for example, there is a potential for further improvement in the signal levels that can be achieved, enabling a standard of imaging of vessels that is not possible today.
Impact of Education and an Antifungal Stewardship Program for Candidiasis at a Thai Tertiary Care Center
Authors: Apisarnthanarak Anucha , Yatrasert Apiwat , Mundy Linda M. ,   Thammasat University Antimicrobial Stewardship Team
Published: May 2010

Background.

We evaluated the impact of education and an antifungal stewardship program for candidiasis on prescribing practices, antifungal consumption, Candida species infections, and estimated costs at a Thai tertiary care hospital.

Methods.

A hospital-wide, quasi-experimental study was conducted for 1.5 years before the intervention and 1.5 years after the implementation of an antifungal stewardship program. Inpatient antifungal prescriptions were prospectively observed, and patients' demographic, clinical, and administrative-cost data were collected. Interventions included education, introduction of an antifungal hepatic and/or renal dose adjustment tool, antifungal prescription forms, and prescription-control strategies.

Results.

After the intervention, there was a 59% reduction in antifungal prescriptions (from 194 to 80 prescriptions per 1,000 hospitalizations; P < .001). Inappropriate antifungal use decreased (from 71% to 24%; P < .001), a sustained reduction in antifungal use was observed (r = 0.83; P < .001), and fluconazole use decreased (from 242 to 117 defined daily doses per 1,000 patient-days; P < .001). Reductions in the incidence of infection with Candida glabrata (r = 0.69; P < .001) and Candida krusei (r = 0.71; P < .001) were observed, whereas the incidence of infection with Candida albicans (r = —0.81; P < .001) increased. Total cost savings were US$31,615 during the 18-month postintervention period.

Conclusions.

Implementation of an antifungal stewardship program was associated with appropriate antifungal drug use, improved resource utilization, and cost savings.
Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women
Authors: Havndrup Ole , Christiansen Michael , Stoevring Birgitte , Jensen Morten , Hoffman‐Bang Jakob , Andersen Paal Skytt , Hasholt Lis , Nørremølle Anne , Feldt‐Rasmussen Ulla , Køber Lars , Bundgaard Henning
Published: May 2010

Aims

Fabry disease, an X‐linked storage disorder caused by defective lysosomal enzyme alpha‐galactosidase A activity, may resemble sarcomere‐gene‐associated hypertrophic cardiomyopathy (HCM). The ‘cardiac variant’ of Fabry disease which only affects the heart may be missed unless specifically tested for.

Methods and results

We evaluated 90 consecutively recruited HCM probands and their relatives. Probands without sarcomere‐gene mutations were tested for alpha‐galactosidase A gene (GLA) mutations. Of the 90 families, 31 (34%) had sarcomere gene mutations and were therefore excluded. In the remaining 59 probands, 3 (5%) had GLA mutations as follows. The first proband, a female with asymmetric septal hypertrophy (ASH), a significant left ventricular outflow tract gradient, and chronic obstructive pulmonary disease, was heterozygous for a novel missense mutation (p.N139S). The second proband, a male with ASH and multiple episodes of ventricular tachycardia, was hemizygous for a missense mutation (p.A156T). His daughter was heterozygous, but had normal enzyme activity. The third proband was a female with ASH, and no other indices of Fabry disease. She was heterozygous for a GLA missense mutation (p.G271S). She had one affected daughter but her two other children were unaffected. The affected daughter had three children, of whom two were also affected—a boy aged 8 and a daughter aged 10 years.

Conclusion

This is the first report of systematic mutation screening of GLA in HCM patients without sarcomere gene mutations. GLA mutations were found in 3/90 (3%) of HCM families and in 2/20 (10%) of females without sarcomere‐gene mutations. None of the probands presented other indices of Fabry disease. This, in combination with putative reversibility of cardiac changes by enzyme replacement therapy, supports systematic testing for Fabry disease. Enzyme measurements are sufficient in men, but genetic testing is needed in women.
Clinical trials update from the American College of Cardiology meeting 2010: DOSE, ASPIRE, CONNECT, STICH, STOP‐AF, CABANA, RACE II, EVEREST II, ACCORD, and NAVIGATOR
Authors: Cleland John G.F. , Coletta Alison P. , Buga Laszlo , Ahmed Daniyal , Clark Andrew L.
Published: May 2010

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the annual meeting of the American College of Cardiology held in March 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. Results from DOSE suggest that giving diuretics using a high‐dose, bolus strategy may be better than using lower doses or a continuous infusion for patients with acute decompensated heart failure. In the ASPIRE study, addition of aliskiren to standard therapy failed to attenuate left ventricular remodelling in post‐MI patients and was associated with more adverse events. In CONNECT, remote monitoring reduced the time from CRT‐D‐ or ICD‐detected events to clinical decision and this was associated with fewer clinic visits and shorter hospitalizations. An analysis from STICH testing the effects of surgical ventricular reconstruction showed no benefit in the sub‐group of patients who achieved a greater reduction in LV volume. STOP‐AF and CABANA did not provide convincing evidence of the effectiveness or safety of catheter ablation for the treatment of AF. RACE II suggests that lenient heart rate control might be as effective as strict rate control in patients with permanent atrial fibrillation. In EVEREST II, a catheter‐based mitral valve repair procedure using the MitraClip® system had similar efficacy to traditional surgery but with fewer short‐term adverse effects. Valsartan reduced progression to diabetes in patients with impaired glucose tolerance but had no effect on cardiovascular events in NAVIGATOR. In ACCORD, strict blood pressure control failed to reduce the risk of overall cardiovascular events in high‐risk diabetic patients.
Clinical trial: five or ten cycles of granulocyte–monocyte apheresis show equivalent efficacy and safety in ulcerative colitis
Authors: DIGNASS A. U. , ERIKSSON A. , KILANDER A. , PUKITIS A. , RHODES J. M. , VAVRICKA S.
Published: May 2010

Aliment Pharmacol Ther 31, 1286–1295

Background  Ulcerative colitis is characterized by leucocyte infiltration into the colonic mucosa. Granulocyte–monocyte apheresis depletes these cells.

Aim  To assess the non‐inferiority of 5–10 apheresis treatments in patients with steroid‐dependent or steroid‐refractory ulcerative colitis.

Methods  A total of 196 adults with moderate–severe ulcerative colitis were randomized 1:1 to 5 (n = 96) or 10 (n = 90) open label apheresis treatments. The primary endpoint was non‐inferiority of clinical activity index score after 12 weeks.

Results  The intent‐to‐treat population comprised 82 and 80 patients for the 5‐ and 10‐treatment groups, respectively. The difference between the two groups in mean clinical activity index was 0.24 with an upper 95% confidence interval of 1.17, which was below a predefined non‐inferiority threshold of 1.33. Clinical activity index score improved from baseline in both groups (from 8.7 to 5.6 with 5 treatments, and from 8.8 to 5.4 with 10), with no significant difference between the groups (P = 0.200). Outcomes for the 5‐ and 10‐treatment groups were similar – Clinical remission: 44% and 40%, respectively (P = 0.636); clinical response: 56% and 59%, respectively (P = 0.753). The treatment was well tolerated in both groups.

Conclusions  This prospective study comparing apheresis regimens in ulcerative colitis demonstrates that 5 treatments were not inferior to 10 treatments in steroid‐refractory or ‐dependent ulcerative colitis.
The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports
Authors: LLANOS L. , MOREU R. , ORTIN T. , PEIRÓ A. M. , PASCUAL S. , BELLOT P. , BARQUERO C. , FRANCÉS R. , SUCH J. , PÉREZ‐MATEO M. , HORGA J. F. , ZAPATER P.
Published: May 2010

Aliment Pharmacol Ther 31, 1337–1345

Background  Drug‐induced liver injury (DILI) profile in most drugs’ available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports.

Aim  To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting.

Methods  Hepatotoxic drugs were identified from product labelling and classified in high‐medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (≥3 × ULN) for drug (ID) and placebo (IC) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE.

Results  The median IC was 10/1000. The high‐medium‐risk drugs’ median ID was significantly higher compared with low‐risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi‐squared test, absolute difference and odds ratio comparing ID and IC identified 35%, 51% and 77% of high‐medium‐risk drugs respectively. Less number of case reports were associated with low‐ than high‐medium‐risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (ID vs. IC) was the strongest predictor of published DILI case reports.

Conclusion  A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.
The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto‐splenomesenteric venous thrombosis
Authors: ORR D. W. , PATEL R. K. , LEA N. C. , WESTBROOK R. H. , O’GRADY J. G. , HEATON N. D. , PAGLIUCA A. , MUFTI G. J. , HENEGHAN M. A.
Published: May 2010

Aliment Pharmacol Ther 31, 1330–1336

Background  Occult myeloproliferative disorders (MPD) are present in 25% of patients with chronic portal, splenic and mesenteric venous thrombosis (PSMVT). A somatic mutation of JAK2 (JAK2V617F) can be used to identify patients with latent MPD.

Aim  We evaluated the prevalence and clinical significance of JAK2V617F in patients with chronic PSMVT.

Methods  Allele‐specific polymerase chain reaction was performed to screen for JAK2V617F.

Results  Thirty‐five patients were tested for JAK2V617F. The underlying pro‐coagulant condition was MPD in seven of 35 (20.0%) patients; other aetiologies included hereditary thrombophilia (n = 5), chronic pancreatitis (n = 2), liver abscess (n = 1) and umbilical vein sepsis (n = 3). The remainder were labelled idiopathic, i.e. 17/35 (48.6%) patients. JAK2V617F was detected in 16/35 (45.7%) patients: seven of seven (100%) with MPD, two of 11 (18.1%) with non‐MPD acquired conditions and seven of 17 (41.2%) with ‘idiopathic’ chronic PSMVT. Mean haemoglobin concentration (P = 0.04), haematocrit (P = 0.04), white cell count (P = 0.002) and platelet count (P = 0.05) were significantly higher in patients with JAK2V617F. None of the seven patients with latent MPD have progressed to overt MPD over median follow‐up of 85 months.

Conclusion  JAK2V617F occurs in 41% of patients with idiopathic chronic portal, splenic and mesenteric venous thrombosis, confirming the presence of latent myeloproliferative disorders, and should form part of the routine pro‐coagulant screen.
Clinical trial: the effects of certolizumab pegol therapy on work productivity in patients with moderate‐to‐severe Crohn’s disease in the PRECiSE 2 study
Authors: FEAGAN B. G. , REILLY M. C. , GERLIER L. , BRABANT Y. , BROWN M. , SCHREIBER S.
Published: May 2010

Aliment Pharmacol Ther 31, 1276–1285

Background  The effect of certolizumab pegol on employment status and work productivity has not been previously assessed.

Aim  To assess the impact of treatment with certolizumab pegol, the only PEGylated, Fab′ TNF antagonist, on work productivity in patients with active Crohn’s disease (CD) from the PRECiSE 2 study.

Methods  Patients (n = 668) with active disease [CD activity index (CDAI) score of 220–450] were treated with open‐label subcutaneous certolizumab pegol 400 mg (week 0, 2, 4). Responders (n = 425) (≥100‐point decrease in CDAI from baseline) were randomized to receive certolizumab pegol 400 mg or placebo every 4 weeks until week 24, with final evaluation at week 26. Patients completed the Work Productivity and Activity Impairment for CD questionnaire (WPAI:CD) and the Inflammatory Bowel Disease Questionnaire (IBDQ) at weeks 0, 6, 16 and 26 and at the withdrawal visit.

Results  Work productivity improved following induction with certolizumab pegol. Between week 6 and 26, certolizumab pegol‐treated patients experienced significant improvement in work productivity compared with placebo recipients (11% and 10% overall improvement in work and activity impairment, respectively). During the maintenance phase, impairments in productivity and activities due to CD were significantly less in the certolizumab pegol group than in the placebo group.

Conclusion  Induction and maintenance therapy with certolizumab pegol significantly improved the work productivity of patients with active CD compared with those in the placebo group.
Faecal lactoferrin – a novel test to differentiate between the irritable and inflamed bowel?
Authors: SIDHU R. , WILSON P. , WRIGHT A. , YAU C. W. H. , D’CRUZ F. A. , FOYE L. , MORLEY S. , LOBO A. J. , MCALINDON M. E. , SANDERS D. S.
Published: May 2010

Aliment Pharmacol Ther 31, 1365–1370

Background  Distinguishing between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) can be challenging.

Aims  To investigate the utility of faecal lactoferrin as a marker of inflammation in patients with IBD, IBS and controls.

Methods  Disease activity in IBD patients was assessed using the modified Harvey–Bradshaw Activity Index. Stool samples were analysed using an ELISA assay.

Results  We recruited 137 patients with IBS, 126 with ulcerative colitis (UC) and 104 with Crohn’s disease (CD), and 98 healthy volunteers. The median ± IQ lactoferrin concentration (μg/g faecal weight) was 0 ± 1.4 for IBS patients, 6.6 ± 42 for UC patients, 4 ± 12.7 for CD patients and 0.5 ± 2 for healthy controls. Lactoferrin levels were significantly higher in IBD patients compared with IBS/healthy controls (P < 0.001). The median lactoferrin concentrations were significantly higher in active UC & CD patients compared with inactive patients (P < 0.001 and P = 0.002 respectively). The sensitivity, specificity, positive and negative predictive values of lactoferrin in distinguishing active IBD from IBS/healthy controls were 67% and 96%, 87% and 86.8% respectively.

Conclusions  Lactoferrin is useful to differentiate between IBD and IBS, and can be used as an adjunct to blood parameters to determine IBD patients who have ongoing inflammation.
Cytometric analysis of oral scrapings of patients with oral lichen planus
Authors: Acha‐Sagredo A. , Jiménez Y. , Bagán J. V. , Echebarria‐Goicouria M. A. , Aguirre‐Urizar J. M.
Published: May 2010

A. Acha‐Sagredo, Y. Jiménez, J. V. Bagán, M. A. Echebarria‐Goicouria and J. M. Aguirre‐Utric analysis of oral scrapings of patients with oral lichen planus

Objective:  Aneuploidy has been associated with malignant and premalignant oral lesions. In the past few years, its application in oral precancerous lesions and its prognostic meaning have been controversial issues. The aim of our study was to characterize alterations in DNA content by automated DNA image cytometry in oral scrapings of patients with oral lichen planus.

Methods:  Cytological samples from 40 patients clinicopathologically diagnosed with oral lichen planus were analysed by DNA image cytometry.

Results:  All the cases were classified as diploid, showing a predominant population of cells with normal DNA content (DNA index, 0.85–1.15). Atrophic/erosive lesions showed a higher percentage of tetraploid cells when compared with reticular/papular lesions but this was not statistically significant (P = 0.09).

Conclusions:  Aneuploidy does not seem a common event in oral lichen planus lesions. However, we consider that the use of DNA image cytometry of oral scrapings may be an easy and helpful methodology in the follow‐up of patients with these lesions.
Non‐trophic effects of oribatid mites on cord‐forming basidiomycetes in soil microcosms
Authors: A'BEAR A. DONALD , BODDY LYNNE , RASPOTNIG GUENTHER , JONES T. HEFIN
Published: May 2010

1. Saprotrophic cord‐forming basidiomycetes are the primary agents of decomposition in forest ecosystems. Collembola and oribatid mites affect fungal growth and foraging, and therefore decomposition, through direct mycelial grazing.

2. Grazing on the fungal species Hypholoma fasciculare, Resinicium bicolor and Phanerochaete velutina by the collembola Folsomia candida, and the oribatid mites Steganacarus magnus, Euzetes globulus and Hermannia gibba was investigated in soil microcosms.

3. Folsomia candida grazed on all fungal species: radial extent of R. bicolor, hyphal coverage of all fungal species, and fractal dimension of R. bicolor and P. velutina were all reduced. Oribatid mites did not graze the fungi but did affect mycelial morphology. Steganacarus magnus caused a reduction in the radial extent of H. fasciculare, and the hyphal coverage and fractal dimension in both H. fasciculare and R. bicolor. Euzetes globulus and H. gibba reduced the hyphal coverage of P. velutina.

4. Oribatid mites are associated with a cornucopia of chemical secretions with possible anti‐fungal properties. Chemical analysis of H. gibba opisthonotal secretions revealed four main compounds, all of which are new to the known spectrum of opisthonotal components. The most abundant was (E)‐β‐farnesene.

5. Treatment effects were species‐specific in terms of both fungal and invertebrate species. This study provides the first evidence of non‐grazing effects of oribatid mites on fungal growth and morphology. This could potentially influence the spatial organisation of mycelium in forest soils and therefore the ability of fungi to locate, colonise and decompose dead organic matter.
SPA: Short peptide analyzer of intrinsic disorder status of short peptides
Authors: Xue Bin , Hsu Wei‐Lun , Lee Jun‐Ho , Lu Hua , Dunker A. Keith , Uversky Vladimir N.
Published: May 2010

Disorder prediction for short peptides is important and difficult. All modern predictors have to be optimized on a preselected dataset prior to prediction. In the succeeding prediction process, the predictor works on a query sequence or its short segment. For implementing the prediction smoothly and obtaining sound prediction results, a specific length of the sequence or segment is usually required. The need of the preselected dataset in the optimization process and the length limitation in the prediction process restrict predictors’ performance. To minimize the influence of these limitations, we developed a method for the prediction of intrinsic disorder in short peptides based on large dataset sampling and statistics. As evident from the data analysis, this method provides more reliable prediction of the intrinsic disorder status of short peptides.
Optimization of the culturing conditions of human umbilical cord blood‐derived endothelial colony‐forming cells under xeno‐free conditions applying a transcriptomic approach
Authors: Zeisberger Steffen M. , Zoller Stefan , Riegel Mariluce , Chen Shuhua , Krenning Guido , Harmsen Martin C. , Sachinidis Agapios , Zisch Andreas H.
Published: May 2010

Establishment of fetal bovine serum (FBS)‐free cell culture conditions is essential for transplantation therapies. Blood‐derived endothelial colony‐forming cells (ECFCs) are potential candidates for regenerative medicine applications. ECFCs were isolated from term umbilical cord blood units and characterized by flow cytometry, capillary formation and responsiveness to cytokines. ECFCs were expanded under standard, FBS‐containing endothelial medium, or transferred to chemically defined endothelial media without FBS. Microarray expression profiling was applied to compare the transcriptome profiles in FBS‐containing versus FBS‐free culture. ECFC outgrowth in standard medium was successful in 92% of cord blood units. The karyotype of expanded ECFCs remained normal. Without FBS, ECFC initiation and expansion failed. Modest proliferation, changes in cell morphology and organization and cell death have been observed after passaging. Gene ontology analysis revealed a broad down‐regulation of genes involved in cell cycle progression and up‐regulation of genes involved in stress response and apoptosis. Interestingly, genes participating in lipid biosynthesis were markedly up‐regulated. Detection of several endothelial cell‐specific marker genes showed the maintenance of the endothelial cell characteristics during serum‐free culture. Although ECFCs maintain their endothelial characteristics during serum‐free culturing, they could not be expanded. Additional supply of FBS‐free media with lipid concentrates might increase the ECFC survival.