bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Amperometric Transducer Electrode with Iridium‐Niobium Binary Alloys
Authors: Matsumoto Toru , Sata Naoaki , Yamabe‐Mitarai Yoko
Published: September 2009

We have discovered that an Ir‐23Nb binary alloy more effectively oxidizes hydrogen peroxide than Ir, Ir‐13Nb, Ir‐17Nb, Ir‐30Nb, Ir‐43Nb, Ir‐62Nb, or Nb. The oxidation capability was determined via cyclic voltammogram measurements of pH‐buffer and hydrogen peroxide. We ascertained that applying a 0.7 V potential produces hydrogen peroxide currents of 9.2 μA/mm2 Ir‐23Nb, 5.3 μA/mm2 Ir, 5.1 μA/mm2 Ir‐17Nb, 3.7 μA/mm2 Ir‐13Nb, 2.0 μA/mm2 Ir‐30Nb, 1.5 μA/mm2 Ir‐43Nb, 0.6 μA/mm2 Ir‐62Nb, and 0.13 μA/mm2 Nb. These results indicate that the effective oxidation of Ir‐23Nb for hydrogen peroxide might be due to its fcc+L12 two‐phase structure and that Ir‐23Nb can be used as an amperometric transducer material.
Template‐Free Galvanic Nanostructuring of Gold Electrodes for Sensitive Electrochemical Biosensors
Authors: Wachholz Falko , Duwensee Heiko , Schmidt Ralf , Zwanzig Michael , Gimsa Jan , Fiedler Stefan , Flechsig Gerd‐Uwe
Published: September 2009

Gold nanostructuring of smooth gold disk‐electrodes has been performed by electrodeposition. FE‐SEM images indicate a strongly enlarged electrochemically active surface of the modified electrodes. This could be approved by the gold oxide reduction peak in cyclic voltammetry. The electrodes were also applied for sequence‐specific DNA detection. For this, complementary single stranded capture probes were immobilized on the electrodes and consecutively hybridized with complementary and noncomplementary [OsO4(bipy)]‐labeled DNA targets. We found that intermediate dehybridization steps did not decrease the sensitivity for the specific target. Moreover, the surface modification increased the voltammetric signal by an approx. factor of 9. Further, an enhanced linear calibration range was observed. The presented simple nanostructuring process holds great promise for many electrochemical sensor applications.
Ferrocene as a Reference Redox Couple for Aprotic Ionic Liquids
Authors: Lewandowski Andrzej , Waligora Lukasz , Galinski Maciej
Published: September 2009

The electrochemical behavior of ferrocene has been studied in a number of room temperature ionic liquids. Diffusion‐controlled, well‐defined anodic and cathodic peaks were found for the Fc/Fc+ (ferrocene/ferrocenium) oxidation/reduction on the gold electrode. Ohmic resistance R between working and auxiliary electrodes was deduced from impedance measurements. Cyclic voltammograms were corrected for the base line current as well as for the ohmic drop (IR). The formal potential 1/2(Epa+Epc) for ferrocene reduction/oxidation in aprotic ionic liquids tested is within a relatively narrow range and may be approximated by the value of 0.527±0.018 V (against the cryptate Ag/Ag+222 in acetonitrile reference). Ferrocene diffusion coefficients, calculated from the peak current dependence on the sweep rate, were of the order of 10−7 cm2 s−1.
Indirect Determination of Trace Tetraborate by Differential Pulse Polarography Using Its Copper Complex and Application to Waste and Drinking Water
Authors: Ünal Ülkü , Somer Güler
Published: September 2009

A new differential pulse polarographic (DPP) method has been developed for the trace determination of boron. Its most stable copper complex is used in 0.5 M KNO3 electrolyte since boron is not electroactive. By continuous addition of tetraborate to copper solution, the copper peak decreased first but then the peak became very small and nearly constant. This point was used for the boron determination. It was found that one mole of copper used two moles of tetraborate. Using this relationship, 1×10−5 M tetraborate could be determined. The quantification limit was 2.5×10−6 M and detection limit was 8×10−7 M. In the presence of complex forming ions such as Pb, Zn, and Cd, the borate found in sample was somewhat smaller because of their reaction with borate. But since their complexes were not as strong as copper, only a few percent of borate were used. No interference was observed in the presence of calcium, chloride and sulfate. This method is applied for the determination of B in borax ore, waste water of borax industries and tap water of Ankara city.
Ultrasensitive Hydrogen Peroxide Biosensor Based on Enzyme Bound to Layered Nonoriented Multiwall Carbon Nanotubes/Polyelectrolyte Electrodes
Authors: Munge Bernard S. , Dowd Richard S. , Krause Colleen E. , Millord Lines N.
Published: September 2009

A sensitive hydrogen peroxide sensor based on horseradish peroxidase covalently attached to layered nonoriented MWNTs modified electrode is presented. Cyclic voltammetry results gave quasi‐reversible FeIII/FeII voltammetry. The electron transfer rate constant (ks) and Michaelis–Menten constant (KM) in pH 7 is 48.8±0.9 s−1 and 0.13±0.05 mM respectively. A linear calibration curve for hydrogen peroxide was obtained up to 120 nM under the optimized conditions with a remarkable detection limit of (S/N=3) 1.5 nM. Results suggest that the nonoriented nanotubes act as electrical conductors and may also provide large surface area facilitating facile electron transfer and excellent electrochemical catalysis.
Preparation and Characterization of GCE Coatings Combining DDDMAB and PDADMAC with FAD and HCM for Electrocatalytic Detection of Oxygen and Sulfur Oxoanions
Authors: Chen Shen‐Ming , Chzo Wen‐Yan , Thangamuthu R.
Published: September 2009

Electrochemically active hybrid coatings based on cationic films, didodecyldimethylammonium bromide (DDDMAB), and poly(diallyldimethylammonium chloride) (PDADMAC) are prepared on glassy carbon electrode surface by cycling the film‐covered electrode repetitively in a pH 7 solution containing flavin adenine dinucleotide (FAD), and anionic hexacyanometalate (HCM) complexes, Fe(CN)63− and Ru(CN)64−. Cyclic voltammetric features of hybrid coatings resemble that of electron transfer process of surface‐confined redox species. Electrochemical quartz crystal microbalance (EQCM) was used to monitor the deposition of FAD on DDDMAB film. Cyclic voltammetric peak potentials of modified electrode were found to be shifted to more negative region with increasing pH of contacting solution with a slope value of 63.3mV per pH unit. The electrocatalytic behavior of FAD‐modified DDDMAB‐coated GCE and hybrid film electrodes was tested towards reduction of oxygen, S2O82−, SO52− and oxidation of SO32−. The application of FAD‐modified DDDMAB‐coated GCE for S2O82− estimation was demonstrated in amperometric mode. The sensitivity and detection limit (S/N=3) were 267.6 μA mM−1 and 2×10−6 M, respectively.
Flow cytometric scoring of micronucleated reticulocytes as a possible high‐throughput radiation biodosimeter
Authors: Liu Libo , Liu Yuguang , Ni Guangying , Liu Shuzheng
Published: September 2009

Micronucleated reticulocyte (MN‐RET) scoring by flow cytometry (FCM) has been used in assessment of the clastogenic effects of chemicals. However, its dose–response to acute whole body irradiation (WBI) at moderate dose rates remains to be established. We show that FCM scoring of MN‐RET in peripheral blood from male ICR mice exposed to WBI X‐ray doses of 0.5–5 Gy at a dose rate of 0.488 Gy/min exhibits a linear dose–response relationship 24, 48, and 72 hr following WBI. Parallel microscopic counting of micronucleated polychromatic erythrocytes (MN‐PCE) in bone marrow smears from the same animals showed similar linear dose–response patterns at the same time points. Indeed, MN‐RET and MN‐PCE were highly correlated at all doses and time points. In view of the speed and accuracy of this method, in addition to the small blood sample size needed for the assay, the flow cytometric protocol for MN‐RET scoring may provide a minimally‐invasive, high throughput radiation biodosimeter. Environ. Mol. Mutagen., 2010. © 2009 Wiley‐Liss, Inc.
Accelerated sediment fluxes by water and tillage erosion on European agricultural land
Authors: Van Oost K. , Cerdan O. , Quine T. A.
Published: September 2009

Soil loss on arable agricultural land is typically an order of magnitude higher than under undisturbed native vegetation. Although there have been several recent attempts to quantify these accelerated fluxes at the regional, continental and even global scale, all of these studies have focused on erosion by water and wind and no large scale assessment of the magnitude of tillage erosion has been made, despite growing recognition of its significance on agricultural land. Previous field scale simulations of tillage erosion severity have relied on use of high resolution topographic data to derive the measures of slope curvature needed to estimate tillage erosion rates. Here we present a method to derive the required measures of slope curvature from low resolution, but large scale, databases and use high resolution topographical datasets for several study areas in the UK to evaluate the reliability of the approach. On the basis of a tillage model and land‐use databases, we estimate the mean gross tillage erosion rates for the part of Europe covered by the CORINE database (6·5% of global cropland) and we obtained an average of 3·3 Mg ha–1 y–1, which corresponds to a sediment flux of 0·35 Pg y–1. Water erosion rates derived for the same area are of a similar magnitude. This redistribution of soil within agricultural fields substantially accelerates soil profile truncation and sediment burial in specific landscape positions and has a strong impact on medium‐term soil profile evolution. It is, therefore, clear that tillage erosion must be accounted for in regional assessments of sediment fluxes and in analyses that employ these in the analysis of land management strategies and biogeochemical cycles. Copyright © 2009 John Wiley & Sons, Ltd.
The impact of exceptional events on erosion, bedload transport and channel stability in a step‐pool channel
Authors: Turowski Jens M. , Yager Elowyn M. , Badoux Alexandre , Rickenmann Dieter , Molnar Peter
Published: September 2009

Sediment transport in the Erlenbach, a small stream with step‐pool morphology in the canton of Schwyz, Switzerland, has been monitored for more than 20 years. During this time three exceptional events (events with high sediment yield and long return times that have a large effect on channel morphology) have impacted the stream and partly or completely rearranged the existing step‐pool morphology. In the aftermath of the events, sediment transport rates at a given discharge and total sediment yield remained elevated for about a year or longer. For the last event, dated on the 20 June 2007, observations of boulder mobility and step destruction were used to interpret channel stability. Boulders with median diameters of up to 135 cm and estimated weights of more than 2·5 tons have moved during the 2007 event. Using hydraulic observations and shear stress calculations boulders up to 65 cm in diameter were predicted to have been fully mobile in peak conditions, even if form resistance and increased critical stresses needed for the initiation of motion in steep streams were taken into account. For two of the events, estimated peak shear stresses at the bed exceeded 1000 Pa, calculated both from observations of the flow hydraulics and from boulder mobility. This suggests that highly energetic flows occur relatively frequently in small, steep streams and that large boulders can be transported by fluvial processes in such streams. The observations have potential significance for hazard risk mitigation, stream engineering and restoration. Copyright © 2009 John Wiley & Sons, Ltd.
Seepage erosion in layered stream bank material
Authors: Lindow Nick , Fox Garey A. , Evans Robert O.
Published: September 2009

Current stream restoration practices often require anthropogenic manipulation of natural field soils to reconstruct stream banks in the absence of stabilizing vegetation. For this study, researchers conducted laboratory experiments on reconstructed, non‐vegetated stream banks with layered soils experiencing seepage. The objective of the study was to determine the effect of seepage, pore water pressure, and bank geometry on erosion and bank stability of layered streambanks. The experimental design consisted of an intermediate‐size soil lysimeter packed with a sandy clay loam top soil and an underlying fine sand layer at three bank slopes (90°, 45° and 26°). Shallow groundwater flow and seepage resulted in bank failure of geometrically stable banks. Pop out failures, liquid deformation, and piping were all observed failure mechanisms in the underlying sand material, dependent on the bank angle. Groundwater seepage processes created small‐scale failures of the underlying sand leading to larger‐scale failures of the overlying sandy clay loam. The underlying sand layer eroded according to the initial bank angle and change in overburden loading. The overlying loam layer failed along linear failure planes. The gradually sloped bank (i.e. 26° slope) failed faster, hypothesized to be due to less confining pressure and greater vertical seepage forces. Researchers analyzed the laboratory experiments using the Bank Stability and Toe Erosion Model, version 4·1. The model calculated an accurate shear surface angle similar to the failure angle observed in the lysimeter tests. The model predicted failure only for the undercut 90° bank slope, and indicated stable conditions for the other geometries. Steeper initial bank slopes and undercut banks decreased the bank factor of safety. The observed failure mechanisms and measured saturation data indicated an interaction between overburden pressure, seepage forces, and bank slope on bank stability. Future bank stability modeling would benefit by incorporating lateral seepage erosion and soil liquefaction prediction calculations. Copyright © 2009 John Wiley & Sons, Ltd.
PPFIA1 and CCND1 are frequently coamplified in breast cancer
Authors: Dancau Ana‐Maria , Wuth Laura , Waschow Marcel , Holst Frederik , Krohn Antje , Choschzick Matthias , Terracciano Luigi , Politis Sotirios , Kurtz Stefan , Lebeau Annette , Friedrichs Kay , Wencke Katharina , Monni Outi , Simon Ronald
Published: September 2009

Recently, amplification of PPFIA1, encoding a member of the liprin family located about 600 kb telomeric to CCND1 on chromosome band 11q13, was described in squamous cell carcinoma of head and neck. Because 11q13 amplification is frequent in breast cancer, and PPFIA1 has been suggested to contribute to mammary gland development, we hypothesized that PPFIA1 might also be involved in the 11q13 amplicon in breast cancer and contribute to breast cancer development. A tissue microarray containing more than 2000 human breast cancers was analyzed for gene copy numbers of PPFIA1 and CCND1 by means of fluorescence in situ hybridization. PPFIA1 amplification was found in 248/1583 (15.4%) of breast cancers. Coamplification with CCND1 was found in all (248/248, 100%) PPFIA1‐amplified cancers. CCND1 amplification without PPFIA1 coamplification was found in additional 117 (4.7%) tumors. Amplification of both PPFIA1 and CCND1 were significantly associated with high‐grade phenotype (P = 0.0002) but were unrelated to tumor stage (P = 0.7066) or nodal stage (P = 0.5807). No difference in patient prognosis was found between 248 CCND1/PPFIA1 coamplified tumors and 117 tumors with CCND1 amplification alone (P = 0.6419). These data show that PPFIA1 amplification occurs frequently in breast cancer. The higher incidence of CCND1 amplification when compared with PPFIA1, the lack of prognostic relevance of coamplifications, and the fact that PPFIA1 amplification was found exclusively in CCND1‐amplified cancers suggest that PPFIA1 gene copy number changes represent concurrent events of CCND1 amplification rather than specific biological incidents. © 2009 Wiley‐Liss, Inc.
Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma
Authors: Freier Kolja , Knoepfle Karl , Flechtenmacher Christa , Pungs Susanne , Devens Frauke , Toedt Grischa , Hofele Christof , Joos Stefan , Lichter Peter , Radlwimmer Bernhard
Published: September 2009

Gene copy number aberrations are involved in oral squamous cell carcinoma (OSCC) development. To delineate candidate genes inside critical chromosomal regions, array‐CGH was applied to 40 OSCC specimens using a microarray covering the whole human genome with an average resolution of 1 Mb. Gene copy number gains were predominantly found at 1q23 (9 cases), 3q26 (11), 5p15 (13), 7p11 (7), 8q24 (17), 11q13 (15), 14q32 (8), 19p13 (8), 19q12 (7), 19q13 (8), and 20q13 (9), whereas gene copy number losses were detected at 3p21‐3p12 (15), 8p32 (11), 10p12 (8), and 18q21‐q23 (10). Subsequent mRNA expression analyses by quantitative real time polymerase chain reaction found high mRNA expression of candidate genes SOX2 in 3q26.33, FSLT3 in 19p13.3, and CCNE1 in 19q12. Tissue microarray (TMA) analyses in a representative OSCC collection found gene copy number gain for SOX2 in 52% (115/223) and for CCNE1 in 31% (72/233) of the tumors. Immunohistochemical analyses on TMA sections of the corresponding proteins detected high expression of SOX2 in 18.1% (49/271) and of CyclinE1 in 23.3% (64/275) of tumors analyzed. These findings indicate that SOX2 and CCNE1 might be activated via gene copy number gain and participate in oral carcinogenesis. The combination of array‐CGH with TMA analyses allows rapid pinpointing of novel promising candidate genes, which might be used as therapeutic stratification markers or target molecules for therapeutic interference. © 2009 Wiley‐Liss, Inc.
Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel‐based morphometry
Authors: Hyde Krista L. , Samson Fabienne , Evans Alan C. , Mottron Laurent
Published: September 2009

Autism spectrum disorder is a complex neurodevelopmental variant thought to affect 1 in 166 [Fombonne (2003): J Autism Dev Disord 33:365–382]. Individuals with autism demonstrate atypical social interaction, communication, and repetitive behaviors, but can also present enhanced abilities, particularly in auditory and visual perception and nonverbal reasoning. Structural brain differences have been reported in autism, in terms of increased total brain volume (particularly in young children with autism), and regional gray/white matter differences in both adults and children with autism, but the reports are inconsistent [Amaral et al. (2008): Trends Neurosci 31:137–145]. These inconsistencies may be due to differences in diagnostic/inclusion criteria, and age and Intelligence Quotient of participants. Here, for the first time, we used two complementary magnetic resonance imaging techniques, cortical thickness analyses, and voxel‐based morphometry (VBM), to investigate the neuroanatomical differences between a homogenous group of young adults with autism of average intelligence but delayed or atypical language development (often referred to as “high‐functioning autism”), relative to a closely matched group of typically developing controls. The cortical thickness and VBM techniques both revealed regional structural brain differences (mostly in terms of gray matter increases) in brain areas implicated in social cognition, communication, and repetitive behaviors, and thus in each of the core atypical features of autism. Gray matter increases were also found in auditory and visual primary and associative perceptual areas. We interpret these results as the first structural brain correlates of atypical auditory and visual perception in autism, in support of the enhanced perceptual functioning model [Mottron et al. (2006): J Autism Dev Disord 36:27–43]. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.
Hemodynamic responses to speech and music in newborn infants
Authors: Kotilahti Kalle , Nissilä Ilkka , Näsi Tiina , Lipiäinen Lauri , Noponen Tommi , Meriläinen Pekka , Huotilainen Minna , Fellman Vineta
Published: September 2009

We used near‐infrared spectroscopy (NIRS) to study responses to speech and music on the auditory cortices of 13 healthy full‐term newborn infants during natural sleep. The purpose of the study was to investigate the lateralization of speech and music responses at this stage of development. NIRS data was recorded from eight positions on both hemispheres simultaneously with electroencephalography, electrooculography, electrocardiography, pulse oximetry, and inclinometry. In 11 subjects, statistically significant (P < 0.02) oxygenated (HbO2) and total hemoglobin (HbT) responses were recorded. Both stimulus types elicited significant HbO2 and HbT responses on both hemispheres in five subjects. Six of the 11 subjects had positive HbO2 and HbT responses to both stimulus types, whereas one subject had negative responses. Mixed positive and negative responses were observed in four neonates. On both hemispheres, speech and music responses were significantly correlated (r = 0.64; P = 0.018 on the left hemisphere (LH) and r = 0.60; P = 0.029 on the right hemisphere (RH)). On the group level, the average response to the speech stimuli was statistically significantly greater than zero in the LH, whereas responses on the RH or to the music stimuli did not differ significantly from zero. This suggests a more coherent response to speech on the LH. However, significant differences in lateralization of the responses or mean response amplitudes of the two stimulus types were not observed on the group level. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.
Hyperphosphorylation of replication protein A in cisplatin‐resistant and ‐sensitive head and neck squamous cell carcinoma cell lines
Authors: Manthey Karoline C. , Glanzer Jason G. , Dimitrova Diana D. , Oakley Greg G.
Published: September 2009

Background

Resistance to chemotherapy is a major limitation in the treatment of head and neck squamous cell carcinomas (HNSCCs), accounting for high mortality rates in patients. Here, we investigated the role of replication protein A (RPA) in cisplatin and etoposide resistance.

Methods

We used 6 parental HNSCC cell lines. We also generated 1 cisplatin‐resistant progeny subline from a parental cisplatin‐sensitive cell line, to examine cisplatin resistance and sensitivity with respect to RPA2 hyperphosphorylation and cell‐cycle response.

Results

Cisplatin‐resistant HNSCC cell levels of hyperphosphorylated RPA2 in response to cisplatin were 80% to 90% greater compared with cisplatin‐sensitive cell lines. RPA2 hyperphosphorylation could be induced in the cisplatin‐resistant HNSCC subline. The absence of RPA2 hyperphosphorylation correlated with a defect in cell‐cycle progression and cell survival.

Conclusion

Loss of RPA2 hyperphosphorylation occurs in HNSCC cells and may be a marker of cellular sensitivities to cisplatin and etoposide in HNSCC. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Role of postoperative irradiation for patients with bilateral cervical nodal metastases from cutaneous melanoma: A critical assessment
Authors: Guadagnolo B. Ashleigh , Myers Jeffrey N. , Zagars Gunar K.
Published: September 2009

Background

The aim of this study was to evaluate the role of regional nodal radiation therapy (RT) for patients with bilateral cervical nodal metastases from melanoma.

Methods

Between 1998 and 2008, 16 patients with bilateral cervical metastases without distant metastases were treated with postoperative RT (30 Gy in 5 fractions delivered twice weekly).

Results

Median follow‐up was 5 months (range, 1–34 months). Median survival was 9 months (95% confidence interval [CI], 0–23 months). Overall survival was 68%, 50%, and 27% at 6, 12, and 24 months, respectively. Regional nodal control was 74% and 64% at 6 and 12 months, respectively. Rates of development of distant metastasis were 60%, 70%, and 90% at 6, 12, and 18 months, respectively. The actuarial rate of RT‐related complications was 49% at 12 months.

Conclusion

The limited life expectancy of patients observed with this disease combined with the high rate of RT‐related complications argue against the routine use of adjuvant RT for regional nodal disease in this setting. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Biochemical and clinical responses after treatment of a catecholamine‐secreting glomus jugulare tumor with gamma knife radiosurgery
Authors: Castrucci William A. , Chiang Veronica L. S. , Hulinsky Ilja , Knisely Jonathan P. S.
Published: September 2009

Background

Functional glomus jugulare tumors (GJTs) are commonly managed with resection. Although primary radiation therapy of functional GJT can provide durable control of tumor growth, little is known of its ability to ablate functional capacity.

Methods and Results

We describe a case of a 47‐year‐old man with a symptomatic norepinephrine‐hypersecreting GJT treated with definitive single‐fraction gamma knife radiosurgery and pharmacologic catecholamine blockade. At a 32‐month follow‐up, he has experienced significant symptomatic improvement, excellent control of local tumor growth, minimal treatment‐related morbidity, and near normalization of catecholamine levels.

Conclusion

Radiosurgery was safe and effective in significantly reducing the functional capacity of a paraganglioma. Care must be taken to avoid inducing a hypertensive crisis during and following treatment, and longer follow‐up will help determine whether and when pharmacologic blockade can be discontinued. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Generation of Functional Human Hepatic Endoderm From Human Induced Pluripotent Stem Cells
Authors: Sullivan Gareth J. , Hay David C. , Park In-Hyun , Fletcher Judy , Hannoun Zara , Payne Catherine M. , Dalgetty Donna , Black James R. , Ross James A. , Samuel Kay , Wang Gang , Daley George Q. , Lee Je-Hyuk , Church George M. , Forbes Stuart J. , Iredale John P. , Wilmut Ian
Published: September 2009

With the advent of induced pluripotent stem cell (iPSC) technology, it is now feasible to generate iPSCs with a defined genotype or disease state. When coupled with direct differentiation to a defined lineage, such as hepatic endoderm (HE), iPSCs would revolutionize the way we study human liver biology and generate efficient “off the shelf” models of human liver disease. Here, we show the “proof of concept” that iPSC lines representing both male and female sexes and two ethnic origins can be differentiated to HE at efficiencies of between 70%–90%, using a method mimicking physiological relevant condition. The iPSC-derived HE exhibited hepatic morphology and expressed the hepatic markers albumin and E-cadherin, as assessed by immunohistochemistry. They also expressed alpha-fetoprotein, hepatocyte nuclear factor-4a, and a metabolic marker, cytochrome P450 7A1 (Cyp7A1), demonstrating a definitive endodermal lineage differentiation. Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin, and alpha-fetoprotein, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and CYP3A4 metabolism, which is essential for drug and toxicology testing.

Conclusion:

This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSCs that exhibits key attributes of hepatocytes, and the potential application of iPSC-derived HE in studying human liver biology. In particular, iPSCs from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionize predictive drug toxicology assays and allow the creation of

in vitro

hepatic disease models. (Hepatology 2009.)
Kupffer Cells Promote Hepatic Steatosis Via Interleukin-1β–Dependent Suppression of Peroxisome Proliferator-Activated Receptor α Activity
Authors: Stienstra Rinke , Saudale Fredy , Duval Caroline , Keshtkar Shohreh , Groener Johanna E. M. , van Rooijen Nico , Staels Bart , Kersten Sander , Müller Michael
Published: September 2009

Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved. To that end, C57Bl/6 mice rendered obese and steatotic by chronic high-fat feeding were treated for 1 week with clodronate liposomes, which cause depletion of Kupffer cells. Loss of expression of marker genes Cd68, F4/80, and Clec4f, and loss of Cd68 immunostaining verified almost complete removal of Kupffer cells from the liver. Also, expression of complement components C1, the chemokine (C-C motif) ligand 6 (Ccl6), and cytokines interleukin-15 (IL-15) and IL-1β were markedly reduced. Importantly, Kupffer cell depletion significantly decreased liver triglyceride and glucosylceramide levels concurrent with increased expression of genes involved in fatty acid oxidation including peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyltransferase 1A (Cpt1α), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1β decreased expression of PPARα and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1β suppressed human and mouse PPARα promoter activity. Suppression of PPARα promoter activity was recapitulated by overexpression of nuclear factor κB (NF-κB) subunit p50 and p65, and was abolished upon deletion of putative NF-κB binding sites. Finally, IL-1β and NF-κB interfered with the ability of PPARα to activate gene transcription.

Conclusion:

Our data point toward important cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage. The effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1β, which suppresses PPARα expression and activity. (Hepatology 2010.)
the Heme Oxygenase 1 Product Biliverdin Interferes With Hepatitis C Virus Replication by Increasing Antiviral Interferon Response
Authors: Lehmann Elisabeth , El-Tantawy Walid Hamdy , Ocker Matthias , Bartenschlager Ralf , Lohmann Volker , Hashemolhosseini Said , Tiegs Gisa , Sass Gabriele
Published: September 2009

The anti-inflammatory and antiapoptotic heme degrading enzyme heme oxygenase-1 (HO-1) has been shown recently to interfere with replication of hepatitis C virus (HCV). We investigated the effect of HO-1 products carbon monoxide (CO), iron and biliverdin on HCV replication using the replicon cell lines Huh-5-15 and LucUbiNeo-ET, stably expressing HCV proteins NS3 through NS5B. Incubation of these cell lines in the presence of the CO donor methylene chloride transiently reduced HCV replication, whereas an increase of iron in cell culture by administration of FeCl3 or iron-saturated lactoferrin did not interfere with HCV replication. Likewise, depletion of iron by deferoxamine during induction of HO-1 by cobalt-protoporphyrin IX did not restore HCV replication. The most prominent effect was observed after incubation of replicon cell lines in the presence of biliverdin. Biliverdin seems to interfere with HCV replication–mediated oxidative stress by inducing expression of antiviral interferons, such as interferon alpha2 and alpha17.

Conclusion:

The antioxidant biliverdin reduces HCV replication

in vitro

by triggering the antiviral interferon response and might improve HCV therapy in the future. (Hepatology 2009.)
Efficacy and Safety of Peginterferon Alfa-2A (40Kd) Plus Ribavirin in Hepatitis C Patients With Advanced Fibrosis and Cirrhosis
Authors: Bruno Savino , Shiffman Mitchell L. , Roberts Stuart K. , Gane Edward J. , Messinger Diethelm , Hadziyannis Stephanos J. , Marcellin Patrick
Published: September 2009

The objective of this study is to determine the efficacy and safety of peginterferon alfa-2a (40KD)/ribavirin in patients with advanced fibrosis. Data from 341 genotype 1/4 patients (99 with bridging fibrosis/cirrhosis) treated for 48 weeks and 1547 genotype 2/3 patients (380 with bridging fibrosis/cirrhosis) treated for 16 or 24 weeks enrolled in three randomized international studies were analyzed. Sustained virological response (SVR) rates decreased progressively from 60% in genotype 1/4 patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis (trend test

P

= 0.0028); and from 76% to 61% and 57%, respectively, in genotype 2/3 patients treated for 24 weeks (trend test

P

< 0.0001). Irrespective of genotype, patients without advanced fibrosis were more likely to have an earlier response to treatment that was associated with higher SVR rates and lower relapse rates during untreated follow-up. Among patients with or without a diagnosis of advanced fibrosis, rates of SVR and relapse were similar for patients with similar responses in the first 12 weeks.

Conclusion:

Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis. However, irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR. (Hepatology 2010.)
Variability in Ethanol Biodisposition in Whites Is Modulated by Polymorphisms in the Adh1b and Adh1c Genes
Authors: Martínez Carmen , Galván Segismundo , Garcia-Martin Elena , Ramos María I. , Gutiérrez-Martín Yolanda , Agúndez José A.G.
Published: September 2009

Association between genetic variations in alcohol-related enzymes and impaired ethanol biodisposition has not been unambiguously proven, and the effect of many newly described polymorphisms remains to be explored. The aims of this study are to elucidate the influence of genetic factors in alcohol biodisposition and effects. We analyzed alcohol pharmacokinetics and biodisposition after the administration of 0.5 g/kg ethanol; we measured ethanol effects on reaction time and motor time in response to visual and acoustic signals, and we analyzed 13 single nucleotide polymorphism (SNPs) in the genes coding forADH1B,ADH1C,ALDH2,andCYP2E1in 250 healthy white individuals. Variability in ethanol pharmacokinetics and biodisposition is related to sex, with women showing a higher area under the curve (AUC) (P= 0.002), maximum concentration (Cmax) (P< 0.001) and metabolic rate (P= 0.001). Four nonsynonymous SNPs are related to decreased alcohol metabolic rates:ADH1Brs6413413 (P= 0.012),ADH1Crs283413 (P< 0.001), rs1693482 (P< 0.001), and rs698 (P< 0.001). Individuals carrying diplotypes combining these mutations display statistically significant decrease in alcohol biodisposition as compared with individuals lacking these mutations. Alcohol effects displayed bimodal distribution independently of sex or pharmacokinetics. Most individuals had significant delays in reaction and motor times at alcohol blood concentrations under 500 mg/L, which are the driving limits for most countries.Conclusion:Besides the identification of new genetic factors related to alcohol biodisposition relevant to whites, this study provides unambiguous identification of diplotypes related to variability in alcohol biodisposition. (Hepatology 2010;51:491–500.)
Therapeutic Rna Manipulation in Liver Disease
Authors: Kerr Thomas A. , Davidson Nicholas O.
Published: September 2009

Posttranscriptional regulation of gene expression is increasingly recognized as a model for inherited and acquired disease. Recent work has expanded understanding of the range of mechanisms that regulate several of these distinct steps, including messenger RNA (mRNA) splicing, trafficking, and/or stability. Each of these pathways is implicated in disease pathogenesis, and each represents important avenues for therapeutic intervention. This review summarizes important mechanisms controlling mRNA processing and the regulation of mRNA degradation, including the role of microRNAs and RNA binding proteins. These pathways provide important opportunities for therapeutic targeting directed at splicing and degradation in order to attenuate genetic defects in RNA metabolism. We will highlight developments in vector development and validation for therapeutic manipulation of mRNA expression with a focus on potential applications in metabolic and immunomediated liver disease. (Hepatology 2010.)
Age-Specific Prognosis Following Spontaneous Hepatitis B E Antigen Seroconversion in Chronic Hepatitis B
Authors: Chen Yi-Cheng , Chu Chia-Ming , Liaw Yun-Fan
Published: September 2009

Hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus infection confers a favorable prognosis, but untoward outcomes may develop in some patients. The impact of the age of HBeAg seroconversion on prognosis is not clearly known. HBeAg-positive patients with biopsy-proven chronic hepatitis B were followed up long-term. Follow-up studies included liver biochemistry, alpha-fetoprotein, and ultrasonography every 3 to 6 months or more frequently if clinically indicated. Of the patients who underwent spontaneous HBeAg seroconversion, the incidences of HBeAg-negative hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen seroclearance were compared between patient groups with different ages at the time of HBeAg seroconversion using Kaplan–Meier survival analysis and Poisson regression model. Spontaneous HBeAg seroconversion was documented in 508 patients. Of the 483 patients who had no evidence of cirrhosis or HCC at the time of HBeAg seroconversion, HBeAg seroconversion occurred before age 30 in 218 patients (group A), between age 31 and 40 in 199 patients (group B), and after age 40 in 66 patients (group C). The 15-year cumulative incidences of HBeAg-negative hepatitis, cirrhosis, and HCC increased with increasing age of HBeAg seroconversion, the lowest being in group A (31.2%, 3.7%, and 2.1%, respectively) and highest being in group C (66.7% [

P

< 0.0001], 42.9% [

P

<0.0001], and 7.7% [

P

= 0.29], respectively). The hazard ratio of HBeAg-negative hepatitis, cirrhosis, and HCC was 2.95, 17.6, and 5.22, respectively, in group C compared with group A.

Conclusion:

Patients with HBeAg seroconversion before age 30 have excellent prognosis, whereas patients with delayed HBeAg seroconversion after age 40 have significantly higher incidences of HBeAg-negative hepatitis, cirrhosis, and HCC. (Hepatology 2010.)
Prevalence of Hepatitis B Surface Antigen Among Refugees Entering the United States Between 2006 and 2008
Authors: Rein David B. , Lesesne Sarah B. , O'Fallon Ann , Weinbaum Cindy M.
Published: September 2009

The Centers for Disease Control and Prevention recommends hepatitis B surface antigen (HBsAg) testing to identify chronic hepatitis B virus infection for foreign-born persons from countries or regions with HBsAg prevalence of ≥2%. However, limited data exist to indicate which countries meet this definition. To address this data gap, we estimated the HBsAg prevalence among refugees entering the United States between 2006 and 2008. We contacted state refugee health coordinators and asked them to report the number of refugees, country of origin, and HBsAg prevalence among refugees screened in their jurisdiction during the most recently available 12-month period prior to August 2008. We pooled data across jurisdictions and calculated the prevalence for any country with more than 30 refugees entering the United States, and where this level of data was not available by country, continents were considered. Of the 47 jurisdictions contacted, we received basic information from 31, with nine jurisdictions reporting HBsAg prevalence by country of origin applicable to 31,980 refugees (approximately 42% of refugees entering the United States during the observation period). We estimated an HBsAg prevalence of 2.8% (95% confidence interval 2.6%-3.0%) for refugees overall. Of the 37 countries with 30 or more refugees entering the United States, 25 had a prevalence of ≥2%. Prevalence was highest among refugees from Africa and Southeast Asia, and lowest among refugees from the Middle East and South/Central America. In the eight countries for which we had comparison data, six had lower HBsAg prevalence than in 1991. (Hepatology 2009.)
Remission in schizophrenia: one‐year Italian prospective study of risperidone long‐acting injectable (RLAI) in patients with schizophrenia or schizoaffective disorder
Authors: Rossi Alessandro , Bagalà Anna , Del Curatolo Vincenzo , Scapati Francesco , Bernareggi Micaela Maria , Giustra Maria Grazia
Published: September 2009

Objectives

To evaluate the maintenance of efficacy of risperidone long‐acting injectable (RLAI) in stable patients with schizophrenia or schizoaffective disorders. The prevalence of patients who met standardized remission criteria will be also evaluated as well as the predictors factors of remission according to psychopathological, psychosocial and subjective correlates.

Methods

52‐week, open‐label prospective trial in 347 stable patients switching directly to RLAI from any previous antipsychotic treatment.

Results

One year of treatment was completed by 70% of patients. Positive and Negative Syndrome Scale (PANSS) total and subscale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) scores improved from baseline at each assessment visit (p < 0.001, p < 0.001 and p < 0.05, respectively). Drug Attitude Inventory 30 (DAI30) scores improved significantly from month 3 onwards. 32% of patients met sustained remission at week 52. In a logistic regression model less severe positive and negative PANSS scores at baseline predicted remission (p < 0.001). RLAI treatment was well tolerated: one‐third of patients reported mild to moderate adverse events (AEs). Eleven patients (3.2%) discontinued treatment due to an AE. No significant weight gain (p = 0.093) was reported.

Conclusions

RLAI treatment up to one year improved symptoms and global functioning versus baseline, indicating that an established and accepted antipsychotic therapy can enable patients with schizophrenia to achieve and maintain remission. Copyright © 2009 John Wiley & Sons, Ltd.
Improving interpolation of daily precipitation for hydrologic modelling: spatial patterns of preferred interpolators
Authors: Kurtzman Daniel , Navon Shilo , Morin Efrat
Published: September 2009

Detailed hydrologic models require high‐resolution spatial and temporal data. This study aims at improving the spatial interpolation of daily precipitation for hydrologic models. Different parameterizations of (1) inverse distance weighted (IDW) interpolation and (2) A local weighted regression (LWR) method in which elevation is the explanatory variable and distance, elevation difference and aspect difference are weighting factors, were tested at a hilly setting in the eastern Mediterranean, using 16 years of daily data. The preferred IDW interpolation was better than the preferred LWR scheme in 27 out of 31 validation gauges (VGs) according to a criteria aimed at minimizing the absolute bias and the mean absolute error (MAE) of estimations. The choice of the IDW exponent was found to be more important than the choice of whether or not to use elevation as explanatory data in most cases. The rank of preferred interpolators in a specific VG was found to be a stable local characteristic if a sufficient number of rainy days are averaged. A spatial pattern of the preferred IDW exponents was revealed. Large exponents (3) were more effective closer to the coast line whereas small exponents (1) were more effective closer to the mountain crest. This spatial variability is consistent with previous studies that showed smaller correlation distances of daily precipitation closer to the Mediterranean coast than at the hills, attributed mainly to relatively warm sea‐surface temperature resulting in more cellular convection coastward. These results suggest that spatially variable, physically based parameterization of the distance weighting function can improve the spatial interpolation of daily precipitation. Copyright © 2009 John Wiley & Sons, Ltd.
Assessment of runoff and sediment yield in the Miyun Reservoir catchment by using SWAT model
Authors: Xu Z. X. , Pang J. P. , Liu C. M. , Li J. Y.
Published: September 2009

The Soil and Water Assessment Tool (SWAT) was used to simulate the transport of runoff and sediment into the Miyun Reservoir, Beijing in this study. The main objective was to validate the performance of SWAT and the feasibility of using this model as a simulator of runoff and sediment transport processes at a catchment scale in arid and semi‐arid area in North China, and related processes affecting water quantity and soil erosion in the catchment were simulated. The investigation was conducted using a 6‐year historical streamflow and sediment record from 1986 to 1991; the data from 1986 to 1988 was used for calibration and that from 1989 to 1991 for validation. The SWAT generally performs well and could accurately simulate both daily and monthly runoff and sediment yield. The simulated daily and monthly runoff matched the observed values satisfactorily, with a Nash‐Sutcliffe coefficient of greater than 0·6, 0·9 and a coefficient of determination 0·75, 0·9 at two outlet stations (Xiahui and Zhangjiafen stations) during calibration. These values were 0·6, 0·85 and 0·6, 0·9 during validation. For sediment simulation, the efficiency is lower than that for runoff. Even so, the Nash‐Sutcliffe coefficient and coefficient of determination were greater than 0·48 and 0·6 for monthly sediment yield during calibration, and these values were greater than 0·84 and 0·95 during validation. Sensitivity analysis shows that sensitive parameters for the simulation of discharge and sediment yield include curve number, base flow alpha factor, soil evaporation compensation factor, soil available water capacity, soil profile depth, surface flow lag time and channel re‐entrained linear parameter, etc. Copyright © 2009 John Wiley & Sons, Ltd.
CDK8 expression in 470 colorectal cancers in relation to β‐catenin activation, other molecular alterations and patient survival
Authors: Firestein Ron , Shima Kaori , Nosho Katsuhiko , Irahara Natsumi , Baba Yoshifumi , Bojarski Emeric , Giovannucci Edward L. , Hahn William C. , Fuchs Charles S. , Ogino Shuji
Published: September 2009

Alterations in the Wnt/β‐catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin‐dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for β‐catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including β‐catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase‐2 (COX‐2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE‐1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with β‐catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer‐specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03–2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18–3.56; p = 0.011) that was adjusted for potential confounders including β‐catenin, COX‐2, FASN, LINE‐1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and β‐catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.