bluuebunny/crossref_metadata_2025 huggingface dataset:
Bipolar Vulnerability and Extreme Appraisals Of Internal States: A Computerized Ratings Study
Authors: Dodd Alyson L. , Mansell Warren , Morrison Anthony P. , Tai Sara
Published: September 2011

A recent integrative cognitive model proposed that multiple, extreme, personalized, positive and negative appraisals of internal states predispose to maintain and exacerbate bipolar symptoms. This study aimed to directly assess conviction in a range of positive and negative appraisals of internal states suggested by the model, by using a laboratory‐based computerized task. In a student sample (n = 68), a history of hypomania was associated with more positive and less negative appraisals of internal states, and a history of depression was associated with more negative appraisals and less positive appraisals of internal states. The sample was then split into three groups for comparison: bipolar risk (n = 18), depression risk (n = 20) and controls (n = 30). Relative to controls, the bipolar risk group made more extreme ratings of catastrophic appraisals of low activation states and tended to make more extreme ratings of appraisals of high activation states. The depression risk group scored higher on a range of negative appraisals of low activation states. These findings provide tentative support for the role of both positive and negative, extreme, personalized appraisals of internal states in hypomania and depression. Copyright © 2011 John Wiley & Sons, Ltd.

Key Practitioner Message

This study investigates putative cognitive vulnerability factors for both hypomania and depression.

A number of associations were found between positive and negative appraisals of internal states and both a history of hypomania and depression.

These results complement previous findings in both analogue and clinical populations that extreme, personalized, positive and negative appraisals of internal states are associated with bipolar symptomatology.

Taken together, these findings could translate into practice, as these appraisals could be targeted in psychological interventions.
Advanced Roll‐to‐Roll Plasma‐Enhanced CVD Silicon Carbide Barrier Technology for Protection from Detrimental Gases
Authors: Zambov L. , Shamamian V. , Weidner K. , Loboda M.
Published: September 2011

The demand for low‐cost transparent gas and moisture barrier materials initiates many activities in the area of roll‐to‐roll (R2R), CVD, thin film technology. The present article is an overview on the elaboration of plasma‐enhanced (PE)CVD technology for R2R manufacturing of amorphous silicon carbide (SiC) barrier coatings applied on polymers. A prototype R2R PECVD reactor is designed and built for uniform coatings deposition on large area web‐substrates. A key feature is the incorporation of the Penning discharge plasma source (PDPS) to provide magnetically confined, high‐density plasma (HDP) with no excessive heat. Coatings are grown on a variety of polymer substrates using trimethylsilane ((CH3)3SiH) as the main organic precursor for delivery of active SiC species in the gas phase during deposition. A variety of analytical techniques are utilized to correlate process operating factors and plasma chemistry with coating composition and properties, in particular with the barrier performance and durability of barrier coated films (BCFs). The developed R2R PECVD technology demonstrates significant achievements in barrier performance with water vapor transmission rate (WVTR) of less than 5 × 10−4 g m−2 day−1 and durability of BCFs for more than 500 h under damp‐heat conditions of 85 °C and 85% relative humidity (RH). Manufactured BCFs can be competitively implemented for protection against detrimental gasses in various applications, such as drug and food packaging, and flexible electronic devices, such as thin film batteries and solar cells, liquid‐crystal (LCD), and light‐emitting diode (LED) displays.
An ant colony optimisation algorithm for aggregated multicast based on minimum grouping model
Authors: Zhu Fangjin , Wang Hua
Published: September 2011

The tree‐based delivery structure of the traditional Internet protocol multicast requires each on‐tree router to maintain a forwarding state for a group. This leads to a state scalability problem when large numbers of concurrent groups exist in a network. To address this state scalability problem, a novel scheme called aggregated multicast has recently been proposed, in which multiple groups are forced to share one delivery tree. In this paper, we define the aggregated multicast problem based on the minimum grouping model, and propose an ant colony optimisation algorithm. The relative fullness of the tree is defined according to the characteristics of the minimum grouping problem and is introduced as an important component in identifying the aggregation fitness function between two multicast groups. New pheromone update rules are designed based on the aggregation fitness function. To improve the convergence time of the algorithm, we use the changes (brought by each group) in the relative fullness of the current tree as the selection heuristic information. The impact of the relative fullness of the tree is analysed using the hypothesis test, and simulation results indicate that introducing relative fullness to the fitness function can significantly improve the optimisation performance of the algorithm. Compared with other heuristic algorithms, our algorithm has better optimisation performance and is more suitable for scenarios with larger bandwidth waste rates. Copyright © 2011 John Wiley & Sons, Ltd.
Extracellular matrix and perineuronal nets in CNS repair
Authors: Kwok Jessica C.F. , Dick Gunnar , Wang Difei , Fawcett James W.
Published: September 2011

A perineuronal net (PNN) is a layer of lattice‐like matrix which enwraps the surface of the soma and dendrites, and in some cases the axon initial segments, in sub‐populations of neurons in the central nervous system (CNS). First reported by Camillo Golgimore than a century ago, the molecular structure and the potential role of this matrix have only been unraveled in the last few decades. PNNs are mainly composed of hyaluronan, chondroitin sulfate proteoglycans, link proteins, and tenascin R. The interactions between these molecules allow the formation of a stable pericellular complex surrounding synapses on the neuronal surface. PNNs appear late in development co‐incident with the closure of critical periods for plasticity. They play a direct role in the control of CNS plasticity, and their removal is one way in which plasticity can be re‐activated in the adult CNS. In this review, we examine the molecular components and formation of PNNs, their role in maturation andsynaptic plasticity after CNS injury, and the possible mechanisms of PNN action. © 2011 Wiley Periodicals, Inc. Develop Neurobiol 71: 1073‐1089, 2011
IL‐33 synergizes with TCR and IL‐12 signaling to promote the effector function of CD8+ T cells
Authors: Yang Qianting , Li Gang , Zhu Yibei , Liu Lin , Chen Elizabeth , Turnquist Hēth , Zhang Xueguang , Finn Olivera J. , Chen Xinchun , Lu Binfeng
Published: September 2011

The effector functions of CD8+ T cells are influenced by tissue inflammatory microenvironments. IL‐33, a member of the IL‐1 family, acts as a danger signal after its release during cell necrosis. The IL‐33/ST2 axis has been implicated in various Th2 responses. Its role in CD8+ T‐cell‐mediated immune response is, however, not known. Here we find that type 1 cytotoxic T (Tc1) cells cultured in vitro unexpectedly express high levels of the IL‐33 receptor ST2. Interestingly, the expression of ST2 in Tc1 cells is dependent on T‐bet, a master Th1/Tc1 transcription factor. In addition, IL‐33 enhances TCR‐triggered IFN‐γ production. IL‐33 together with IL‐12 can stimulate IFN‐γ production in Tc1 cells. Moreover, IL‐33 synergizes with IL‐12 to promote CD8+ T‐cell effector function. The synergistic effect of IL‐33 and IL‐12 is partly mediated by Gadd45b. Together, these in vitro data establish a novel role of IL‐33 in promoting effector type 1 adaptive immune responses.
A Phospha‐Wittig Route to 5‐Phosphaphenanthrene
Authors: Wang Huaiqiu , Zhao Weining , Zhou Yang , Duan Zheng , Mathey François
Published: September 2011

The reaction of tributylphosphane with a 7‐(2′‐formyl‐2‐biphenylyl)phosphanorbornadiene P‐W(CO)5 complex leads to the 5‐phosphaphenanthrene P‐W(CO)5 complex via an intramolecular phospha‐Wittig condensation. This complex is stable enough for detection by 31P NMR spectroscopy but cannot be isolated due to its high reactivity. It is trapped by addition of MeOH or cycloaddition with 2,3‐dimethylbutadiene or a nitrileimine. The adducts were characterized by X‐ray crystal structure analysis.
Synthesis, Structure, and C–C Cross‐Coupling Activity of (Amine)bis(phenolato)iron(acac) Complexes
Authors: Hasan Kamrul , Dawe Louise N. , Kozak Christopher M.
Published: September 2011

A series of (amine)bis(phenolato)iron(III)acac complexes has been prepared and characterized. Reaction of Fe(acac)3 with the diprotonated linear tetradentate proligand N,N′‐bis(4,6‐di‐tert‐butyl‐2‐methylphenol)‐N,N′‐dimethyl‐1,2‐diaminoethane, H2[L1], and tripodal tetradentate ligand precursors dimethylaminoethylamino‐N,N‐bis(2‐methylene‐4,6‐di‐tert‐butylphenol), H2[L2], dimethylaminoethylamino‐N,N‐bis(2‐methylene‐4‐methyl‐6‐tert‐butylphenol), H2[L3], 2‐methoxyethylamino‐N,N‐bis(2‐methylene‐4,6‐di‐tert‐butylphenol), H2[L4], 2‐methoxyethylamino‐N,N‐bis(2‐methylene‐4‐methyl‐6‐tert‐butylphenol), H2[L5], and 2‐methoxyethylamino‐N,N‐bis(2‐methylene‐4,6‐dimethylphenol), H2[L6], produces the distorted octahedral FeIII complexes [L1]Fe(acac) (1), [L2]Fe(acac) (2), [L3]Fe(acac) (3), [L4]Fe(acac) (4), [L5]Fe(acac) (5), and [L6]Fe(acac) (6). In all of these complexes, the phenolato oxygen atoms are cis‐oriented. The paramagnetic FeIII complexes 1–6 were also characterized by UV/Vis and IR spectroscopy, mass spectrometry, cyclic voltammetry, and magnetic measurements. Single crystal X‐ray molecular structures have been determined for complexes 1, 2, 3, 5, and the proligand H2[L6]. Preliminary investigations of complexes 1–6 for catalytic cross‐coupling reactions of aryl Grignard reagents with cyclic and acyclic secondary alkyl halides and benzyl halides were performed. While the activity for cyclohexyl chlorides and bromides was high, cross‐coupling of benzyl halides was moderate and 2‐bromo‐ and 2‐chlorobutane gave poor yields of cross‐coupled product.
Small Substituents Make Large Differences: Aminopyrimidinyl Phosphanes Undergoing C–H Activation
Authors: Farsadpour Saeid , Ghoochany Leila Taghizadeh , Sun Yu , Thiel Werner R.
Published: September 2011

Palladium complexes synthesised from (C6H5CN)2PdCl2and (2‐aminopyrimidinyl)phosphanes show different coordination modes depending on the nature of the amino substituent attached to the pyrimidine ring. WhereasP,N‐coordination is observed for primary and secondary amino groups, tertiary amino groups lead to C–H activation at the pyrimidine ring. These differences result in strongly different catalytic activities in the Suzuki–Miyaura coupling reaction. The palladium complexes were characterised spectroscopically and bymeans of X‐ray structural analysis. DFT calculations were carried out to differ between the electronic and steric effects that are responsible for their behaviour in catalysis.
Standardization of vegetable oils composition to be used as oleochemistry feedstock through a selective hydrogenation process
Authors: Zaccheria Federica , Psaro Rinaldo , Ravasio Nicoletta , Bondioli Paolo
Published: September 2011

Selective hydrogenation over pre‐reduced 8% Cu/SiO2 catalysts has been carried out on a series of non‐food oils methylesters. The catalyst shows a very high diene:monoene selectivity, thus allowing one to reduce not only the linolenic component, but also the linoleic one in this way enriching the oil in oleic acid and avoiding a contemporary increase in stearic acid concentration. This treatment improves the oxidation stability of the oil while keeping acceptable viscosity and cold properties and can be used to standardize a wide variety of different available feedstock.

Practical applications: Vegetable oils from different sources can be used as primary, secondary (when they are residues of other processes), or tertiary (post‐consumer wastes) feedstock for the chemical industry. Their composition can be very different as far as unsaturated components are concerned. This variability is an issue because it can lead to multiple products and moreover the unsaturation level, that is the iodine value, is strongly related to oxidation unstability. The process we propose here allows one to standardize the oil composition improving the oxidation stability and keeping acceptable fluidity. The very mild experimental conditions, 4–6 atm of H2 and 160–180°C, the use of a non‐toxic and cheap metal, make this process sustainable and easily viable, e.g., in hardening plants.
5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin
Authors: d'Ischia Marco , Napolitano Alessandra , Pezzella Alessandro
Published: September 2011

5,6‐Dihydroxyindoles, the key building blocks of eumelanin biopolymers, hold promise as versatile molecular systems for the design and development of new functional aromatic scaffolds, biomimetic polymers, and nanomaterials with tailored optical and electronic properties. During the past decade, research into the photophysics, synthesis, π electron manipulation, and reaction behavior of 5,6‐dihydroxyindoles has expanded beyond the traditional boundaries of biology and medicine to involve physicists, organic chemists, and materials scientists. This review presents the latest advances in 5,6‐dihydroxyindole chemistry from a new perspective. Touching only upon themes at the periphery of eumelanin research, it seeks rather to throw light on the chemical and photophysical features of this peculiar π electron system as an unexplored conceptual and practical platform on which synthetic creativity and rational design might generate a range of chemically diverse molecular scaffolds.
Oxidative Coupling Reactions of 1,3‐Diarylpropene Derivatives to Dibenzo[a,c]cycloheptenes by PIFA
Authors: Hackelöer Kristina , Schnakenburg Gregor , Waldvogel Siegfried R.
Published: September 2011

The oxidative cyclization reactions of a variety of α‐benzylcinnamates can be selectively performed with hypervalent iodine as an oxidant. The dibenzo[a,c]cycloheptenes were isolated in up to 55 % yield. When an oxo substrate is applied, the yield was significantly increased. With this synthetic approach, a central intermediate for the synthesis of metasequirin‐B was obtained in three steps from very simple starting materials. For this transformation, both aryl moieties have to be activated.
Inside the Shrine of the Lion Goddess
Authors: El‐Sayed Rafed
Published: September 2011

Athribis is the last major unexplored temple complex of Ancient Egypt. A long‐term binational project aims to get closer to uncovering the secrets of this unique limestone temple.
Cooled by Light
Authors: Vogl Ulrich , Weitz Martin
Published: September 2011

Using laser bombardment, physicists are developing a powerful method for lowering the temperature of atomic gases at very high pressures. For materials research, this opens new possibilities – and, in the long term, may even lead to the development of new freezers.
The Voice of Emotions
Authors: Zimmermann Elke
Published: September 2011

Research on the role of emotions in acoustic communication and its evolution has been neglected for a long time. Ongoing comparative studies of nonhuman mammals and man are now providing new and surprising insights.
Zur Dimensionierung von Nagelwänden
Authors: Renk Daniel , Kolymbas Dimitrios
Published: September 2011

Nagelwände sind Verbundkörper aus Boden und Stahlstäben und können als Gewichts‐Stützmauern den Erddruck aufnehmen. Ihre Standsicherheit wird aufgrund von Starrkörperbruchmechanismen unter Berücksichtigung von Nagelzugkräften nachgewiesen, wobei Gleitfuge und Nägel in etwa senkrecht zueinander stehen. Die dadurch bedingte Kinematik vermag jedoch kaum, Zugkräfte in den Nägeln zu mobilisieren, was einen Widerspruch darstellt. Bei dem hier vorgeschlagenen Nachweis werden Spannungen im Verbundkörper betrachtet, wodurch dieser Widerspruch behoben wird.

On the design of nailed retaining walls

Nailed retaining walls are composites consisting of soil and steel rods. They act as retaining walls and resist earth pressure. Usual design methods are based on the consideration of rigid block failure mechanisms, where the shear band and the nails intersect at nearly 90°. However, this mechanism cannot mobilize tensile forces in the nails, what is contradictory to the assumption of the existing methods. We propose a new design‐method which is based on the consideration of stress within the composite and, thus, removes the afore mentioned contradiction.
Explicit modeling of cone and strip footing penetration under drained and undrained conditions using a visco‐hypoplastic model
Authors: Qiu Gang , Grabe Jürgen
Published: September 2011

In this paper a visco‐hypoplastic model, which can describe viscous behavior including creep, relaxation and rate dependency of cohesive soils, is implemented in the form of a user subroutine VUMAT in Abaqus/Explicit to model soil‐structure interaction in clayey soil. The VUMAT subroutine is verified with a UMAT subroutine by back‐calculating standard element tests. In addition, an uncoupled analysis strategy, using effective parameters to calculate the stresses in nearly incompressible materials, is implemented in user subroutines to model the soil under undrained conditions. A strategy of scaling the reference creep rate is used to improve the efficiency of the explicit analyses. Furthermore, the penetration process of a cone penetration test (CPT) in a cohesive soil is simulated to investigate the effects of penetration velocity on the cone penetration resistance. Finally, the user subroutine VUMAT is used together with the coupled Eulerian‐Lagrangian method to investigate a strip footing problem.

Explizite Modellierung des Eindringens einer Sonde und eines Streifenfundaments unter dränierten und undränierten Bedingungen mittels eines visko‐hypoplastischen Stoffgesetzes

In diesem Artikel wird ein visko‐hypoplastisches Modell vorgestellt, welches das viskose Verhalten einschließlich Kriechen, Relaxation und Viskosität eines bindigen Bodens beschreiben kann. Dieses Modell wird in der Form einer “user Subroutine” VUMAT in Abaqus/Explicit implementiert, damit die Anwendungen der CEL‐Methode zur Simulation der Ton‐Struktur‐Interaktion erweitert werden können. Die VUMAT‐Routine wird mithilfe der UMAT‐Routine durch Nachrechnung von Elementversuchen überprüft. Zusätzlich wird eine entkoppelte Analysestrategie in die VUMAT‐Routine implementiert, um eine Modellierung des Bodens unter undränierten Bedingungen zu ermöglichen. Durch Skalierung der Referenzkriechrate wird die Effizienz der expliziten Analysen verbessert. Danach wird der Penetrationsvorgang einer Drucksonde in bindigen Böden mithilfe der FE‐Modellierung simuliert, um den Einfluss der Eindringgeschwindigkeit auf den Drucksondierwiderstand zu untersuchen. Schließlich wird mit dem Eindrücken eines Streifenfundaments in den Untergrund ein komplexes geotechnisches Randwertproblem mit Verwendung der gekoppelten Euler‐Lagrange‐Methode mit der VUMATRoutine untersucht.
Zur Gleitkreisberechnung ohne Lamellen nach DIN 4084
Authors: Goldscheider Michael , Hettler Achim
Published: September 2011

Mit den in DIN 4084:2009‐01 angegebenen Formeln zur Berechnung von Gleitkreisen ohne Lamelleneinteilung, die auf Fröhlich zurückgehen, wird der sogenannte Ausnutzungsgrad der Bemessungswiderstände nicht in Übereinstimmung mit seiner Definition erhalten. In diesem Beitrag wird ein statisch korrektes und den heutigen Sicherheitsdefinitionen entsprechendes Berechnungsverfahren vorgestellt. Es beruht auf den elementaren Grundlagen der Statik starrer Scheiben. Wie allgemein bei gekrümmten Gleitlinien sind statische Annahmen notwendig; diese werden begründet und sind nicht stärker als beim Lamellenverfahren. Wie beim Lamellenverfahren ist im Allgemeinen eine Iteration erforderlich. Die Methode wird auch auf verankerte Böschungen erweitert. Hierbei kann man wahlweise ohne Iteration die erforderliche Ankerkraft oder mit Iteration den Ausnutzungsgrad bei gewählter Ankerkraft bestimmen. Die Methode lässt sich zeichnerisch nach den Regeln der grafischen Statik oder rein rechnerisch mit Handrechnung durchführen. Die rechnerische Methode eignet sich auch für ein Computerprogramm. Die Anwendung wird am Beispiel einer verankerten Baugrubenböschung ausführlich vorgeführt.

Slip circle stability calculation without slices based on DIN 4084

Using the formulas represented in DIN 4084:2009‐01 and adopted from Fröhlich to calculate slip circle stability without slices the so‐called degree of utilization of the design values of resistances is not obtained in accordance with its present definition. In this paper, a statically correct method of calculation corresponding to the current safety definitions is outlined. It is deduced from the principles of statics of rigid bodies. As generally for circular slip lines some statical assumptions must be introduced; those are explained and are not more restrictive than in the case of the slice methods. As for the slice methods, iteration is necessary, in general, to solve the equations. The method is extended for the problem of anchored slopes. Optionally, the required anchor force can be determined without iteration or the degree of utilization can be obtained for a given anchor force with iteration. The method can be performed graphically taking into account the rules of graphical statics or analytically by short basic calculation. The analytical algorithm also is compatible with computer programming. The application is demonstrated by an example of an anchored excavation slope.
A MARKOV MODEL TO ESTIMATE SALMONELLA MORBIDITY, MORTALITY, ILLNESS DURATION, AND COST
Authors: Herrick Robert L. , Buchberger Steven G. , Clark Robert M. , Kupferle Margaret , Murray Regan , Succop Paul
Published: September 2011

Approximately 690 000–1 790 000 Salmonella cases, 20 000 hospitalizations, and 400 deaths occur in the USA annually, costing approximately $2.6bn. Existing models estimate morbidity, mortality, and cost solely from incidence. They do not estimate illness duration or use time as an independent cost predictor. Existing models may underestimate physician visits, hospitalizations, deaths, and associated costs. We developed a Markov chain Monte Carlo model to estimate illness duration, physician/emergency room visits, inpatient hospitalizations, mortality, and resultant costs for a given Salmonella incidence. Interested parties include society, third‐party payers, health providers, federal, state and local governments, businesses, and individual patients and their families. The marginal approach estimates individual disease behavior for every patient, explicitly estimates disease duration and calculates separate time‐dependent costs. The aggregate approach is a Markov equivalent of the existing models; it assumes average disease behavior and cost for a given morbidity/mortality. Transition probabilities were drawn from a meta‐analysis of 53 Salmonella studies. Both approaches were tested using the 1993 Salmonella typhimurium outbreak in Gideon, Missouri. This protocol can be applied to estimate morbidity, mortality and cost of specific outbreaks, provide better national Salmonella burden estimates, and estimate the benefits of reducing Salmonella risk. Copyright © 2011 John Wiley & Sons, Ltd.
Serum ferritin concentration and transferrin saturation before liver transplantation predict decreased long-term recipient survival
Authors: Weismüller Tobias J. , Kirchner Gabriele I. , Scherer Marcus N. , Negm Ahmed A. , Schnitzbauer Andreas A. , Lehner Frank , Klempnauer Jürgen , Schlitt Hans J. , Manns Michael P. , Strassburg Christian P.
Published: September 2011

Serum ferritin (SF) concentration is a widely available parameter used to assess iron homeostasis. It has been described as a marker to identify high-risk patients awaiting liver transplantation (LT) but is also elevated in systemic immune-mediated diseases, metabolic syndrome, and in hemodialysis where it is associated with an inferior prognosis. This study analyzed whether SF is not only a predictor of liver-related mortality prior to LT but also an independent marker of survival following LT. In a dual-center, retrospective study, a cohort of 328 consecutive first-LT patients from Hannover Medical School, Germany (2003-2008, follow-up 1260 days), and 82 consecutive LT patients from Regensburg University Hospital, Germany (2003-2007, follow-up 1355 days) as validation cohort were analyzed. In patients exhibiting SF ≥365 μg/L versus <365 μg/L prior to LT, 1-, 3-, and 5-year post-LT survival was 73.3% versus 81.1%, 64.4% versus 77.3%, and 61.1% versus 74.4%, respectively (overall survival

P

= 0.0097), which was confirmed in the validation cohort (overall survival of 55% versus 83.3%,

P

= 0.005). Multivariate analyses identified SF ≥365 μg/L combined with transferrin saturation (TFS) <55%, hepatocellular carcinoma, and the survival after LT (SALT) score as independent risk factors for death. In patients with SF concentrations ≥365 μg/L and TFS <55%, overall survival was 54% versus 74.8% in the remaining group (

P

= 0.003). In the validation cohort, it was 28.6% versus 72% (

P

= 0.017), respectively.

Conclusion:

SF concentration ≥365 μg/L in combination with TFS <55% before LT is an independent risk factor for mortality following LT. Lower TFS combined with elevated SF concentrations indicate that acute phase mechanisms beyond iron overload may play a prognostic role. SF concentration therefore not only predicts pre-LT mortality but also death following LT. (Hepatology 2011;)
Indeterminate 1-2-cm nodules found on hepatocellular carcinoma surveillance: Biopsy for all, some, or none?
Authors: Khalili Korosh , Kim Tae Kyoung , Jang Hyun-Jung , Yazdi Leyla Kochak , Guindi Maha , Sherman Morris
Published: September 2011

In the latest hepatocellular carcinoma (HCC) management guidelines by the American Association for the Study of Liver Diseases, biopsy is advocated for all nodules deemed indeterminate after imaging work-up by contrast-enhanced scans. However, the latest guidelines' imaging work-up algorithm has been shown to improve sensitivity of characterization of HCC for 1-2-cm nodules, decreasing the proportion of HCCs that remain indeterminate after imaging work-up. We undertook a study of 1-2-cm indeterminate nodules to determine what proportions are malignant and which variables can be used to limit biopsy to a subset of nodules at higher risk of malignancy. Eighty consecutive patients with 93 indeterminate nodules were included. Final diagnosis was established in 85 nodules, with 13 malignant (9 by biopsy, 4 by growth) and 72 benign (stability of ≥18 months). Cause of liver disease, ethnicity, size, arterial hypervascularity, venous hypoenhancement, and presence of synchronous typical HCC were analyzed by univariate logistic analysis to determine significant predictors of malignancy. Rate of malignancy among indeterminate 1-2-cm nodules was found to be 14%-23%. Only arterial hypervascularity [odds ratio (OR), 3.7) and presence of synchronous HCC (OR, 7.1) were significant predictors of malignancy. A strategy of limiting biopsy to nodules that had either feature would result in 23 biopsies and potentially detect 8 of 13 malignant nodules, yielding a sensitivity of 62% and specificity of 79%.

Conclusion:

The prevalence of malignancy among 1-2-cm indeterminate nodules is low (14%-23%), and biopsy of all such nodules results in many negative results. Limiting biopsy to nodules with arterial hypervascularity or in the presence of a synchronous typical HCC would detect the majority of HCCs while substantially reducing the number of biopsies. (Hepatology 2011)
Tenascin-C: A novel mediator of hepatic ischemia and reperfusion injury
Authors: Kuriyama Naohisa , Duarte Sergio , Hamada Takashi , Busuttil Ronald W. , Coito Ana J.
Published: September 2011

Hepatic ischemia/reperfusion (IRI) injury remains a major challenge in clinical orthotopic liver transplantation (OLT). Tenascin-C (Tnc) is an extracellular matrix protein (ECM) involved in various aspects of immunity and tissue injury. Using a Tnc-deficient mouse model, we present data that suggest an active role for Tnc in liver IRI. We show that Tnc-deficient mice have a reduction in liver damage and a significant improvement in liver regeneration after IRI. The inability of Tnc−/− mice to express Tnc significantly reduced the levels of active caspase-3/transferase-mediated dUTP nick end-labeling (TUNEL) apoptotic markers and enhanced the expression of the proliferation cell nuclear antigen (PCNA) after liver IRI. The lack of Tnc expression resulted in impaired leukocyte recruitment and decreased expressions of interleukin (IL)-1β, IL-6, and CXCL2 after liver reperfusion. Tnc-deficient livers were characterized by altered expression patterns of vascular adhesion molecules, such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 post-IRI. Moreover, matrix metalloproteinase-9 (MMP-9) synthesis, which facilitates leukocyte transmigration across vascular barriers in liver IRI, was markedly down-regulated in the absence of Tnc. We also show that Tnc is capable of inducing MMP-9 expression in isolated neutrophils through Toll-like receptor 4. Therefore, our data suggest that Tnc is a relevant mediator of the pathogenic events underlying liver IRI. The data also support the view that studies aimed at further understanding how newly synthesized ECM molecules, such as Tnc, participate in inflammatory responses are needed to improve therapeutic approaches in liver IRI. (Hepatology 2011)
Field-practice study of sorafenib therapy for hepatocellular carcinoma: A prospective multicenter study in Italy
Authors: Iavarone Massimo , Cabibbo Giuseppe , Piscaglia Fabio , Zavaglia Claudio , Grieco Antonio , Villa Erica , Cammà Calogero , Colombo Massimo
Published: September 2011

A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (

P

< 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival.

Conclusion:

Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy. (Hepatology 2011)
Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking
Authors: Wu Chuanghong , Gilroy Richard , Taylor Ryan , Olyaee Mojtaba , Abdulkarim Bashar , Forster Jameson , O'Neil Maura , Damjanov Ivan , Wan Yu-Jui Yvonne
Published: September 2011

The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1–positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator-activated receptor (PPAR) α and β as well as steroid regulatory element-binding protein (SREBP)-1c was decreased in HCV-infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels.

Conclusion:

Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury. (Hepatology 2011)
Activation of liver X receptor increases acetaminophen clearance and prevents its toxicity in mice
Authors: Saini Simrat P.S. , Zhang Bin , Niu Yongdong , Jiang Mengxi , Gao Jie , Zhai Yonggong , Lee Jung Hoon , Uppal Hirdesh , Tian Hui , Tortorici Michael A. , Poloyac Samuel M. , Qin Wenxin , Venkataramanan Raman , Xie Wen
Published: September 2011

Overdose of acetaminophen (APAP), the active ingredient of Tylenol, is the leading cause of drug-induced acute liver failure in the United States. As such, it is necessary to develop novel strategies to prevent or manage APAP toxicity. In this report, we reveal a novel function of the liver X receptor (LXR) in preventing APAP-induced hepatotoxicity. Activation of LXR in transgenic (Tg) mice or by an LXR agonist conferred resistance to the hepatotoxicity of APAP, whereas the effect of LXR agonist on APAP toxicity was abolished in LXR-deficient mice. The increased APAP resistance in LXR Tg mice was associated with increased APAP clearance, increased APAP sulfation, and decreased formation of toxic APAP metabolites. The hepatoprotective effect of LXR may have resulted from the induction of antitoxic phase II conjugating enzymes, such as Gst and Sult2a1, as well as the suppression of protoxic phase I P450 enzymes, such as Cyp3a11 and Cyp2e1. Promoter analysis suggested the mouse

Gst

isoforms as novel transcriptional targets of LXR. The suppression of

Cyp3a11

may be accounted for by the inhibitory effect of LXR on the PXR-responsive transactivation of

Cyp3a11

. The protective effect of LXR in preventing APAP toxicity is opposite to the sensitizing effect of pregnane X receptor, constitutive androstane receptor, and retinoid X receptor alpha.

Conclusion:

We conclude that LXR represents a potential therapeutic target for the prevention and treatment of Tylenol toxicity. (Hepatology 2011)
Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice
Authors: Zeng Xin , Lin Yong , Yin Chuan , Zhang Xin , Ning Bei-Fang , Zhang Qing , Zhang Jun-Ping , Qiu Lei , Qin Xiao-Ran , Chen Yue-Xiang , Xie Wei-Fen
Published: September 2011

Hepatocyte nuclear factor-1alpha (HNF1α) is one of the key transcription factors of the HNF family, which plays a critical role in hepatocyte differentiation. Substantial evidence has suggested that down-regulation of HNF1α may contribute to the development of hepatocellular carcinoma (HCC). Herein, human cancer cells and tumor-associated fibroblasts (TAFs) were isolated from human HCC tissues, respectively. A recombinant adenovirus carrying the

HNF1α

gene (AdHNF1α) was constructed to determine its effect on HCC

in vitro

and

in vivo

. Our results demonstrated that HCC cells and HCC tissues revealed reduced expression of HNF1α. Forced reexpression of HNF1α significantly suppressed the proliferation of HCC cells and TAFs and inhibited the clonogenic growth of hepatoma cells

in vitro

. In parallel, HNF1α overexpression reestablished the expression of certain liver-specific genes and microRNA 192 and 194 levels, with a resultant increase in p21 levels and induction of G2/M arrest. Additionally, AdHNF1α inhibited the expression of cluster of differentiation 133 and epithelial cell adhesion molecule and the signal pathways of the mammalian target of rapamycin and transforming growth factor beta/Smads. Furthermore, HNF1α abolished the tumorigenicity of hepatoma cells

in vivo

. Most interestingly, intratumoral injection of AdHNF1α significantly inhibited the growth of subcutaneous HCC xenografts in nude mice. Systemic delivery of AdHNF1α could eradicate the orthotopic liver HCC nodules in nonobese diabetic/severe combined immunodeficiency mice.

Conclusion:

These results suggest that the potent inhibitive effect of HNF1α on HCC is attained by inducing the differentiation of hepatoma cells into mature hepatocytes and G2/M arrest. HNF1α might represent a novel, promising therapeutic agent for human HCC treatment. Our findings also encourage the evaluation of differentiation therapy for tumors of organs other than liver using their corresponding differentiation-determining transcription factor. (Hepatology 2011)
Transforming Growth Factor–Beta Signaling Promotes Hepatocarcinogenesis Induced by P53 Loss
Authors: Morris Shelli M. , Baek Ji Yeon , Koszarek Amanda , Kanngurn Samornmas , Knoblaugh Sue E. , Grady William M.
Published: September 2011

Hepatocellular carcinoma (HCC) results from the accumulation of deregulated tumor suppressor genes and/or oncogenes in hepatocytes. Inactivation of

TP53

and inhibition of transforming growth factor–beta (TGF–β) signaling are among the most common molecular events in human liver cancers. Thus, we assessed whether inactivation of TGF–β signaling, by deletion of the TGF–β receptor, type II (Tgfbr2), cooperates with

Trp53

loss to drive HCC formation.

Albumin–cre

transgenic mice were crossed with floxed

Trp53

and/or floxed

Tgfbr2

mice to generate mice lacking p53 and/or Tgfbr2 in the liver. Deletion of

Trp53

alone (

Trp53

KO

) resulted in liver tumors in approximately 41% of mice by 10 months of age, whereas inactivation of

Tgfbr2

alone (

Tgfbr2

KO

) did not induce liver tumors. Surprisingly, deletion of

Tgfbr2

in the setting of p53 loss (

Trp53KO;Tgfbr2

KO

) decreased the frequency of mice with liver tumors to around 17% and delayed the age of tumor onset. Interestingly,

Trp53

KO

and

Trp53KO;Tgfbr2

KO

mice develop both HCC and cholangiocarcinomas, suggesting that loss of p53, independent of TGF–β, may affect liver tumor formation through effects on a common liver stem cell population. Assessment of potential mechanisms through which TGF–β signaling may promote liver tumor formation in the setting of p53 loss revealed a subset of

Trp53

KO

tumors that express increased levels of alpha–fetoprotein. Furthermore, tumors from

Trp53

KO

mice express increased TGF–β1 levels compared with tumors from

Trp53KO;Tgfbr2

KO

mice. Increased phosphorylated Smad3 and ERK1/2 expression was also detected in the tumors from

Trp53

KO

mice and correlated with increased expression of the TGF–β responsive genes,

Pai1

and

Ctgf

.

Conclusion:

TGF–β signaling paradoxically promotes the formation of liver tumors that arise in the setting of p53 inactivation. (Hepatology 2012)
Glucocorticoids Increase Interleukin–6–Dependent Gene Induction by Interfering With the Expression of the Suppressor of Cytokine Signaling 3 Feedback Inhibitor
Authors: Dittrich Anna , Khouri Christina , Sackett Sara Dutton , Ehlting Christian , Böhmer Oliver , Albrecht Ute , Bode Johannes G. , Trautwein Christian , Schaper Fred
Published: September 2011

Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well–documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross–talk between glucocorticoids and interleukin–6 (IL–6) in the liver. IL–6 exerts pro–inflammatory as well as anti–inflammatory properties and is a main inducer of the acute–phase response. The balance between the proinflammatory and anti–inflammatory activities of IL–6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well–known feedback inhibitor of IL–6 signaling. Here, it is demonstrated that glucocorticoids enhance IL–6–dependent γ–fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down–regulation of SOCS3 protein expression. Consequently, in SOCS3–deficient cells glucocorticoids do not affect IL–6–induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL–6–dependent γ–fibrinogen expression is not influenced by glucocorticoid treatment.

Conclusion:

Glucocorticoids interfere with IL–6–induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute–phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute–phase gene induction. (Hepatology 2012;55:256–266)
Cost–Effectiveness of Hepatitis C Virus Antiviral Treatment for Injection Drug User Populations
Authors: Martin Natasha K. , Vickerman Peter , Miners Alec , Foster Graham R. , Hutchinson Sharon J. , Goldberg David J. , Hickman Matthew
Published: September 2011

Injecting drug use is the main risk of hepatitis C virus (HCV) transmission in most developed countries. HCV antiviral treatment (peginterferon–α + ribavirin) has been shown to be cost–effective for patients with no reinfection risk. We examined the cost–effectiveness of providing antiviral treatment for injecting drug users (IDUs) as compared with treating ex/non–IDUs or no treatment. A dynamic model of HCV transmission and disease progression was developed, incorporating: a fixed number of antiviral treatments allocated at the mild HCV stage over 10 years, no retreatment after treatment failure, potential reinfection, and three baseline IDU HCV chronic prevalence scenarios (20%, 40%, and 60%). We performed a probabilistic cost–utility analysis estimating long–term costs and outcomes measured in quality adjusted life years (QALYs) and calculating the incremental cost–effectiveness ratio (ICER) comparing treating IDUs, ex/non–IDUs, or no treatment. Antiviral treatment for IDUs is the most cost–effective option in the 20% and 40% baseline chronic prevalence settings, with ICERs compared with no treatment of £521 and £2,539 per QALY saved, respectively. Treatment of ex/non–IDUs is dominated in these scenarios. At 60% baseline prevalence, treating ex/non–IDUs is slightly more likely to be the more cost–effective option (with an ICER compared with no treatment of £6,803), and treating IDUs dominated due to high reinfection. A sensitivity analysis indicates these rankings hold even when IDU sustained viral response rates as compared with ex/non–IDUs are halved.

Conclusion

: Despite the possibility of reinfection, the model suggests providing antiviral treatment to IDUs is the most cost–effective policy option in chronic prevalence scenarios less than 60%. Further research on how HCV treatment for injectors can be scaled up and its impact on prevalence is warranted. (Hepatology 2012)
Simulated watershed scale impacts of corn stover removal for biofuel on hydrology and water quality
Authors: Cibin R. , Chaubey I. , Engel B.
Published: September 2011

Ethanol from corn stover is expected to play an important role in achieving the Energy Independence and Security Act 2007 target of 136.25 billion liters (36 billion gallons) of biofuel by 2022. The 2010 USDA biofuel strategic report estimates that 16.3 billion liters (4.3 billion gallons) of biofuel from crop residues such as corn stover and straw is possible. Corn stover is expected to provide the majority of the estimated biofuel from crop residues, especially from the Midwestern US Corn Belt. A major concern related to removing corn stover is potential negative hydrologic and water quality impacts. The overall goal of this study was to estimate the watershed scale environmental impacts of corn stover removal in an agricultural watershed in the Midwest US. Soil and Water Assessment Tool was used to simulate the impacts associated with three corn stover removal rates (38%, 52% and 70%). The stream flow, nitrate and mineral phosphorus loading were reduced, and sediment and organic nitrogen loading were increased at the watershed outlet with all three stover removal scenarios. The stream flow was reduced by 1.4%, 2.0% and 2.7% from the baseline scenario (no stover removed) at 38%, 52% and 70% stover removal rates, respectively. The sediment loading increased by 19.7%, 22.5% and 29.0%, organic nitrogen increased by 0.8%, 2.0% and 5.5%, mineral phosphorus decreased by 11.7%, 15.5% and 21.0%, and nitrate decreased by 2.0%, 3.2% and 5.3% from the baseline scenario at the watershed outlet with 38%, 52% and 70% stover removal rates, respectively. The model results also indicate that the watershed response to stover removal is sensitive to watershed characteristics and management inputs, such as, slope and amount of fertilizer applied. Copyright © 2011 John Wiley & Sons, Ltd.