bluuebunny/crossref_metadata_2025 huggingface dataset:
Histopathological correlates of magnetic resonance imaging–defined chronic perinatal white matter injury
Authors: Riddle Art , Dean Justin , Buser Joshua R. , Gong Xi , Maire Jennifer , Chen Kevin , Ahmad Tahir , Cai Victor , Nguyen Thuan , Kroenke Christopher D. , Hohimer A. Roger , Back Stephen A.
Published: June 2011

Objective:

Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white‐matter injury (WMI) in preterm survivors, the histopathological features of MRI‐defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.

Methods:

We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically‐defined lesions with contrast‐weighted and diffusion‐weighted high‐field ex vivo MRI data.

Results:

Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ∼2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI‐defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non‐necrotic injury. High‐field MRI defined 2 novel hypointense signal abnormalities on T2‐weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity.

Interpretation:

These studies support the potential of high‐field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors. ANN NEUROL 2011
New crosslinked polyurethane elastomers with various physical properties from natural rubber derivatives
Authors: Kébir Nasreddine , Campistron Irène , Laguerre Albert , Pilard Jean‐François , Bunel Claude
Published: June 2011

New hydroxytelechelic cis‐1,4‐oligoisoprenes exhibiting variable values and distributions of the hydroxyl functionality were successfully prepared. The synthesis reactions involved chemical modifications of carbonyl telechelic cis‐1,4‐polyisoprene, which was obtained by controlled degradation of synthetic or natural rubber. These new oligomers were reacted with toluene diisocyanate to elaborate crosslinked polyurethane elastomers. The thermomechanical properties of the prepared polyurethanes were investigated. The results show a strong relationship between the chemical structures and properties. This work mainly shows the potentiality of making new crosslinking polyurethane materials with controlled and various properties from natural rubber, a renewable resource. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Polycarbonateurethane films containing complex of copper(II) catalyzed generation of nitric oxide
Authors: Zhao Haiyang , Feng Yakai , Guo Jintang
Published: June 2011

Nitric oxide (NO) is a well known potent antiplatelet agent, and its continuous release will effectively prevent the adhesion of platelets on artificial blood vessel walls. In this paper, polycarbonateurethane (PCU) with lipophilic Cu(II)‐complex (Cu(II)‐DTTCT) blending films were prepared and used as catalyst to generate NO from nitrite. The mechanical properties of PCU films blended with Cu(II)‐DTTCT were characterized by tensile strength measurement. The tensile stress and Young's modulus of PCU films blending with Cu(II)‐DTTCT increased, however, the elongation at break decreased compared with corresponding PCU films. The NO generation was investigated in vitro in the presence of NaNO2 and ascorbic acid in PBS (pH = 7.4) at 37°C. The flux of NO generation was quantitatively measured by Griess assay. NO flux and velocity increased with the increase of NaNO2 concentration, the concentration of ascorbic acid in PBS and the amount of Cu(II) in the films. The loss of Cu(II) from blending film surfaces was found during the in vitro NO generation experiments, which resulted in the decrease of NO flux in the second run. The PCU film could catalyze continually generation of NO for two days, which will provide a promising approach that enable endogenous NO generation on the surface of the medical devices. The generation of biologically active level of NO at the blood/polymer interface can reduce the risk of thrombosis on the implants. Polycarbonateurethane films with NO generation function may be used as high thromboresistant blood contacting materials or coating. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Effect of Reduced c‐Kit Signaling on Bone Marrow Adiposity
Authors: Turner Russell T. , Wong Carmen P. , Iwaniec Urszula T.
Published: June 2011

c‐Kit (CD117) is required for normal differentiation of osteoblasts from bone marrow stromal cells and for normal bone formation. Osteoblasts and adipocytes originate from a common progenitor cell, and a reciprocal relationship in differentiation of the two lineages is often observed. Therefore, the effects of abnormal c‐kit signaling on bone marrow adiposity and adipocyte precursor pool size were evaluated in mouse strains with loss of function mutations in kit receptor or kit ligand. Additionally, to determine whether short‐duration pharmacological disruption of kit signaling influences bone marrow adiposity, we administered the kit receptor antagonist gleevec (imatinib mesilate) for 1 week to middle aged (13‐month‐old) male rats known to have high levels of bone marrow fat. Compared to wild‐type littermates, adipocytes were absent and adipocyte precursors greatly reduced in bone marrow from kit receptor‐deficient KitW/W‐ν mice. Administration of secreted kit ligand to membrane‐associated kit ligand‐deficient KitSl/Sl‐d mice was ineffective in inducing bone marrow adipogenesis. These findings suggest that activation of kit receptor by the membrane‐associated form of kit ligand is required for kit signaling to promote bone marrow adipogenesis in mice. Rats treated with gleevec had lower adipocyte density compared to age‐matched controls, suggesting that kit signaling is required to maintain normal bone marrow adiposity. Taken together, our results indicate that c‐Kit signaling plays an important but previously unsuspected role in regulating bone marrow adiposity. Anat Rec, , 2011. © 2011 Wiley‐Liss, Inc.
Co‐variation in frequency and severity of cardiovascular and skeletal defects in Sprague‐Dawley rats after maternal administration of dimethadione, the N‐demethylated metabolite of trimethadione
Authors: Weston Andrea D. , Brown Nigel A. , Ozolinš Terence R.S.
Published: June 2011

BACKGROUND: The anticonvulsant trimethadione is a potent inducer of ventricular septation defects, both clinically and in rodents. Teratogenicity requires its N‐demethylation to dimethadione, the proximate teratogen. It was previously demonstrated trimethadione only induced membranous ventricular septation defects in rat (Fleeman et al., 2004), and our present goal is to determine whether direct administration of dimethadione increases the incidence and severity of septation defects. METHODS: Pregnant Sprague‐Dawley rats were divided into five groups and administered either distilled water (control) or four different regimens of dimethadione. The core treatment was 300 mg/kg dimethadione b.i.d. on gestation day 9, 10 with additional groups given one additional dose of dimethadione 12 hr earlier, 12 hr later or two additional doses 12 hr earlier and later. Caesarian sections occurred on gestation day 21 and fetuses were examined for standard developmental toxicity endpoints. RESULTS: The broadest dosing regimen yielded the highest incidence and the most severe heart and axioskeletal findings with a decrease in mean fetal body weight. The overall incidence of ventricular septation defects was 74%, of which 68% were membranous and 9% muscular. Outflow tract anomalies (17%) were also observed, as were malformations of the axioskeleton (97%), but not of the long bones, and of particular interest was the high incidence of sternoschesis. CONCLUSIONS: Unlike trimethadione, dimethadione induces more serious muscular septation defects that are believed to be more clinically relevant. This, when taken together with the high incidence of total septation anomalies suggests dimethadione is useful for the study of chemically induced ventricular septation defects. Birth Defects Res (Part B) 92:206–215, 2011. © 2011 Wiley‐Liss, Inc.
Lebensdauerbemessung im Betonbau
Authors: Müller Harald S. , Vogel Michael
Published: June 2011

Ein effizientes Lebenszyklusmanagement von Betonbauwerken erfordert die Dauerhaftigkeitsbemessung beim Neubau bzw. die Lebensdauerprognose für Bestandsbauten. Sie ermöglichen gleichermaßen eine wirtschaftliche wie auch eine nachhaltigkeitsbezogene Optimierung einer Konstruktion bzw. einzuleitender Erhaltungsmaßnahmen. Der vorliegende Beitrag behandelt schwerpunktmäßig die Dauerhaftigkeitsbemessung. Dabei werden weniger die Schadensmechanismen auf Bauteilebene beleuchtet als vielmehr die Methodik des Übergangs vom Bauteil zur Gesamtkonstruktion. Ebenfalls wird dargestellt, wie die Interaktion dauerhaftigkeitsrelevanter Einwirkungen modelliert werden kann und wie singuläre Risiken (z. B. Spannstahlkorrosion) in einer Gesamtbetrachtung berücksichtigt werden können.

Service life design in concrete construction – From the deterioration process related to components to safety analysis of whole structures

Relevant methods for the lifetime management of concrete structures are the design for durability relating to new structures and the lifetime prediction relating to existing structures. These methods allow to manage the entire lifetime of a concrete structure while avoiding cost‐intensive maintenance measures and corresponding downtimes. This paper focuses on the design for durability. Major emphasis is put on the presentation of methods to describe the behaviour of the concrete structure as a whole resulting from the integration of the deterioration effects on the member level. Based on the fact that different deterioration mechanisms occur in combination with each other, procedures for modelling interactions and singular risks (e. g. corrosion of tendons) are dealt with as well in this paper.
Überdeckelung der Autobahn A59 in Duisburg
Authors: Erdmann Jörg , Müller Thilo , Holz Malte
Published: June 2011

Der Ausbau von Verkehrswegen gehört zu den ingenieurtechnischen Aufgaben, welche die erforderliche Leistungsfähigkeit unserer verkehrlichen Infrastruktur sicherstellen. Am Beispiel der Abdeckelung der Autobahn A59 im innerstädtischen Bereich von Duisburg wird gezeigt, wie durch eine besonders auf die bauliche Umsetzung ausgerichtete Planung mit Entwicklung maßgebender Detailpunkte eine Herstellung erfolgen konnte, welche sich bezüglich Bauablauf und Zeitaufwand als optimiert ergeben hat, eine wirtschaftliche Lösung darstellt und den Verkehr auf der Autobahn weitestgehend unbeeinträchtigt belassen hat.
Bemessungsregeln und Ausführungshinweise für Schubkerven im Holz‐Beton‐Verbundbau
Authors: Schönborn Florian , Flach Michael , Feix Jürgen
Published: June 2011

In der vorliegenden Arbeit werden theoretische und experimentelle Untersuchungen zur Beschreibung des lokalen und globalen Tragverhaltens von Holz‐Beton‐Verbunddecken, die an der Universität Innsbruck durchgeführt werden, zusammengefasst. Dabei werden auf der Basis eines Versuchsprogrammes Rechenformate zur lokalen Bemessung der einzelnen Verbindungen sowie der gesamten Verbundträger abgeleitet.

Design Rules and Details for Construction of Grooves in Timber‐Concrete‐Composite Constructions

This article presents a scientific work on timber concrete floor systems with grooves. Experimental and theoretical works done at university Innsbruck are presented in order to describe the local and global behavior of these shear‐connectors. As a result, all relevant parameters as well as design rules are identified.
Ein Bemessungskonzept für unbewehrte und faserbewehrte Tunnelinnenschalen
Authors: Saurer Erich , Höser Sebastian , Mattle Bruno
Published: June 2011

Aufbauend auf geltenden Richtlinien und Normen wird ein Verfahren für die statische Berechnung und Bemessung unbewehrter und faserbewehrter Tunnelinnenschalen vorgestellt. Das Bemessungskonzept erfordert eine iterative Suche nach dem statischen Gleichgewicht des Tragsystems unter Berücksichtigung nichtlinearen Materialverhaltens. Als Ergebnis liefert das Verfahren nebst den herkömmlichen Nachweisen (Tragfähigkeit und Gebrauchstauglichkeit) Aussagen, ob eine unbewehrte bzw. faserbewehrte Ausführung der Innenschale möglich ist. Im Falle der Notwendigkeit faserbewehrten Innenschalenbetons sind Aussagen bezüglich der erforderlichen Nachrisszugfestigkeit möglich.

A Design Concept for Plain and Fibre‐Reinforced Final Linings of Tunnels

A concept for the design of final tunnel linings on the basis of current standards and guidelines is presented. The proposed method requires an iterative approach towards the equilibrium of the static system considering nonlinear material behaviour in compression and tension. As a result this method returns a design proof either for the unreinforced lining or the fibre‐reinforced lining including the required post crack tensile strength of fibre‐reinforced concrete.
Zu den deutschen Anfängen des Bauens mit Beton
Authors: Stegmann Knut
Published: June 2011

Eugen Dyckerhoff (1844–1924), Kaufmann und Mitinhaber des Bauunternehmens Dyckerhoff & Widmann (später: Dywidag), war einer der bedeutendsten deutschen Betonpioniere des 19. Jahrhunderts. Ab den 1860er Jahren trieb er mit systematischer Grundlagenforschung die Weiterentwicklung des Betons zum anwendungsreifen Baustoff voran. Sein unbewehrter “Stampfbeton” wurde dank geschickter Öffentlichkeitsarbeit mit Vorträgen, Publikationen und Ausstellungsteilnahmen zu einem Standard im deutschen Bauwesen. Unter Dyckerhoffs Führung erschloss die kaufmännisch geprägte Firma Dyckerhoff & Widmann dem Beton immer neue Anwendungsgebiete, angefangen von der Produktion (künstlerischer) Fertigteile über den konstruktiven Ingenieurbau bis zu den repräsentativen Hochbauten des frühen 20. Jahrhunderts.
The intrinsic viscosity of linear DNA
Authors: Tsortos Achilleas , Papadakis George , Gizeli Electra
Published: June 2011

We measured the intrinsic viscosity of very small synthetic DNA molecules, of 20–395 base pairs, and incorporated them in a nearly complete picture for the whole span of molecular weights reported in the literature to date. A major transition is observed at M ∼ 2 × 106. It is found that in the range of ∼ 7 × 103 ≤ M ≤ 2 × 106, the intrinsic viscosity scales as [η] ∼ M1.05, suggesting that short DNA chains are not as rigid as generally thought. The corresponding scaling for the range of 2 × 106 ≤ M ≤ 8 × 1010 is [η] ∼ M0.69. A comparison of our results with existing equations, for much narrower data distributions, is made, and the agreement is very satisfactory considering the huge range of data analyzed here. Experimental concerns such as the effect of ionic strength, polydispersity, temperature, and shear rate are discussed in detail. Some issues concerning the Huggins coefficient, polymer chain stiffness, and the relationship between the Mark–Houwink constants K, α are also presented; it is found that log K = 1.156 − 6.19α. © 2011 Wiley Periodicals, Inc. Biopolymers 95:824–832, 2011.
Duration of hepatic vascular inflow clamping and survival after liver resection for hepatocellular carcinoma
Authors: Ishizuka M , Kubota K , Kita J , Shimoda M , Kato M , Sawada T
Published: June 2011

Background

The aim of this study was to evaluate the influence of the duration of hepatic vascular inflow clamping (Pringle time) on the survival of patients with any type of liver background (not only cirrhosis) undergoing liver resection for hepatocellular carcinoma (HCC).

Methods

Patients who underwent liver resection between April 2000 and December 2008 for HCC using the Pringle manoeuvre were identified retrospectively from an institutional database and divided into two groups: group 1 had a Pringle time of 60 min or less, and group 2 a Pringle time of more than 60 min. Univariable and multivariable analyses were performed to identify predictors of postoperative survival. Kaplan–Meier analysis was used to compare overall survival between the groups.

Results

A total of 357 patients were enrolled; 242 patients had a Pringle time of 60 min or less (group 1), and 115 patients had a Pringle time of more than 60 min (group 2). Patients in group 2 had a shorter overall survival than those in group 1 (P = 0·010). Univariable analyses showed that type of HCC (primary versus recurrent), maximum tumour diameter, hepatic venous infiltration, platelet count, serum protein induced by vitamin K absence or antagonist II level, blood loss (700 ml or less versus more than 700 ml), duration of operation (300 min or less versus more than 300 min) and Pringle time (60 min or less versus more than 60 min) were predictive of postoperative survival. Multivariable analysis indicated that only Pringle time was associated with postoperative survival (odds ratio 1·83, 95 per cent confidence interval 1·08 to 3·10; P = 0·024).

Conclusion

Longer Pringle time is an important predictor of shorter postoperative survival in patients undergoing liver resection for HCC.
Stakeholder Engagement: Defining Strategic Advantage for Sustainable Construction
Authors: Rodriguez‐Melo Alexander , Mansouri S. Afshin
Published: June 2011

Although sustainable development is increasingly becoming a part of business plans, it is unclear what makes the economic, social and environmental dynamics strategically compatible. This research examines which of the following in sustainable development – government policy, managerial attitude and stakeholder engagement – is the most influential on the profitability of companies in the UK construction sector. Quantitative and qualitative analyses were rendered through a survey and semi‐structured interviews. Patterns of ambiguity in legislation were discovered as an obstacle for changing the sector's mind‐set. Stakeholder engagement was identified as the defining factor increasing managers' awareness, helping legislation to be effectively implemented and making sustainability highly appealing to clients. These findings indicate that to gain competitive advantage, companies should embark on long‐term strategic alliances which adopt the proposals of environmental non‐governmental organisations and closely follow public opinion. This, strengthens brand equity, allows for premium pricing, increases market share and maximizes profit. Copyright © 2011 John Wiley & Sons, Ltd and ERP Environment.
Inhibition of myosin II triggers morphological transition and increased nuclear motility
Authors: Szabó Bálint , Ünnep Renáta , Markó Károly , Környei Zsuzsanna , Méhes Előd , Czirók András
Published: June 2011

We investigate the effect of myosin II inhibition on cell shape and nuclear motility in cultures of mouse radial glia‐like neural progenitor and rat glioma C6 cells. Instead of reducing nucleokinesis, the myosin II inhibitor blebbistatin provokes an elongated bipolar morphology and increased nuclear motility in both cell types. When myosin II is active, time‐resolved traction force measurements indicate a pulling force between the leading edge and the nucleus of C6 cells. In the absence of myosin II activity, traction forces during nucleokinesis are diminished below the sensitivity threshold of our assay. By visualizing the centrosome position in C6 cells with GFP‐centrin, we show that in the presence or absence of myosin II activity, the nucleus tends to overtake or lag behind the centrosome, respectively. We interpret these findings with the help of a simple viscoelastic model of the cytoskeleton consisting active contractile and passive compressed elements. © 2011 Wiley‐Liss, Inc.
Regulation of β‐tubulin isotypes by micro‐RNA 100 in MCF7 breast cancer cells
Authors: Lobert Sharon , Jefferson Bianca , Morris Kevin
Published: June 2011

Antimitotic drugs are key components of combination chemotherapy protocols for hematological and solid tumors. The taxanes (e.g., paclitaxel) bind to the β subunit of the tubulin heterodimer and reduce microtubule dynamics, leading to cell cycle arrest in G2/M. The effectiveness of combination chemotherapy is limited by tumor resistance to drugs initially or as a cumulative effect after several cycles of treatment. Because changes in the drug receptor may be linked to drug resistance, we investigated changes in β‐tubulin isotypes in response to paclitaxel treatment in MCF7 breast cancer cells. We found that paclitaxel induced a 2–3 fold increase in mRNA for β‐tubulin IIA and III genes, TUBB2A, and TUBB3. β‐Tubulin class III protein increased; however, β‐tubulin class II protein was not detected in these cells. Paclitaxel treatment following pretreatment with actinomycin D showed that the change in β‐tubulin class III was due to increased transcription and linked to G2/M arrest. The increase in β‐tubulin IIA mRNA was due to both enhanced stability and increased transcription, unassociated with G2/M arrest. We used micro‐RNA superarrays to look for changes in families of micro‐RNAs that might be linked to drug‐induced changes in β‐tubulin isotype mRNA and/or protein. We found a significant decrease in the tumor suppressor, miR‐100, in MCF7 cells in response to paclitaxel treatment. Transfection of MCF7 cells with miR‐100 significantly reduced β‐tubulin I, IIA, IIB and V mRNA and prevented paclitaxel‐induced increases in β‐tubulin isotypes. This is the first report of a micro‐RNA that regulates these specific β‐tubulin isotype mRNAs. © Wiley‐Liss, Inc.
Modelling pipeline for subject‐specific arterial blood flow—A review
Authors: Sazonov Igor , Yeo Si Yong , Bevan Rhodri L. T. , Xie Xianghua , van Loon Raoul , Nithiarasu Perumal
Published: June 2011

In this paper, a robust and semi‐automatic modelling pipeline for blood flow through subject‐specific arterial geometries is presented. The framework developed consists of image segmentation, domain discretization (meshing) and fluid dynamics. All the three subtopics of the pipeline are explained using an example of flow through a severely stenosed human carotid artery. In the Introduction, the state‐of‐the‐art of both image segmentation and meshing is presented in some detail, and wherever possible the advantages and disadvantages of the existing methods are analysed. Followed by this, the deformable model used for image segmentation is presented. This model is based upon a geometrical potential force (GPF), which is a function of the image. Both the GPF calculation and level set determination are explained. Following the image segmentation method, a semi‐automatic meshing method used in the present study is explained in full detail. All the relevant techniques required to generate a valid domain discretization are presented. These techniques include generating a valid surface mesh, skeletonization, mesh cropping, boundary layer mesh construction and various mesh cosmetic methods that are essential for generating a high‐quality domain discretization. After presenting the mesh generation procedure, how to generate flow boundary conditions for both the inlets and outlets of a geometry is explained in detail. This is followed by a brief note on the flow solver, before studying the blood flow through the carotid artery with a severe stenosis. Copyright © 2011 John Wiley & Sons, Ltd.
A hybrid approach for selecting service‐based real‐time composition algorithms in heterogeneous environments
Authors: Estévez‐Ayres Iria , García‐Valls Marisol , Basanta‐Val Pablo , Díez‐Sánchez Jorge
Published: June 2011

Service‐based approach has been successfully applied to distributed environments, modelling them as pieces of functionality that exchange information by means of messages in order to achieve a common goal. The advantages of this approach can be also be applied to distributed real‐time systems, increasing their flexibility and allowing the creation of new brand applications from existing services in the system. If this is an online process, then time‐bounded composition algorithms are needed to not jeopardize the performance of the whole system. Different composition algorithms are studied and proposed, two of them optimal and another two based on heuristics. This paper presents an analytical solution that selects, depending on the structure of the application and on the load of the whole system, the most suitable composition algorithm to be executed in order to obtain a composed application in bounded time. Copyright © 2011 John Wiley & Sons, Ltd.
Double‐blind study comparing doxercalciferol and placebo in vitamin D‐replete CKD patients
Authors: Patel Anita , Robertson John , Darwin Christine , Locay Harold , Añel Ramon , Engstrand Sara , Hunter John , Plone Melissa , Cangiano Jose
Published: June 2011

OBJECTIVE

No well‐controlled studies of the safety and efficacy of active vitamin D analogues have been conducted in vitamin D‐replete (25‐hydroxyvitamin D ≥ 30 ng/mL) patients. This study assessed the safety and efficacy of doxercalciferol in vitamin D‐replete patients with secondary hyperparathyroidism.

METHODS

This was a randomized, double‐blind, placebo‐controlled, parallel study. Twenty‐four vitamin D‐replete (exogenous ergocalciferol or intrinsically replete) patients with elevated intact parathyroid hormone (iPTH) were randomized to receive doxercalciferol or matching placebo capsules for 24 weeks. The dose was regularly titrated to achieve target iPTH levels (CKD Stage 3: ≤ 70 pg/mL; CKD Stage 4: ≤ 110 pg/mL).

RESULTS

Eleven (92%) doxercalciferol patients met the iPTH target range at least once post randomization compared with four (33%) placebo patients. All 12 (100%) doxercalciferol patients achieved a 30% reduction in iPTH at least once post randomization, and more doxercalciferol patients (83%) maintained iPTH within the target range for up to 6 weeks compared with the placebo patients (17%). Doxercalciferol and placebo were well tolerated during the study. No adverse events of hypercalcemia were reported.

CONCLUSIONS

Doxercalciferol was well tolerated and effective in reducing iPTH in vitamin D‐replete CKD patients without accompanying hypercalcemia. Further studies in a larger population of vitamin D‐replete patients are needed.
Carbohydrate‐derived Fulvic acid (CHD‐FA) inhibits Carrageenan‐induced inflammation and enhances wound healing: efficacy and Toxicity study in rats
Authors: Sabi Riaz , Vrey Pieter , van Rensburg Constance E. Jansen
Published: June 2011

The objectives of this study were to evaluate the safety and anti‐inflammatory and wound‐healing characteristics of carbohydrate‐derived fulvic acid (CHD‐FA) in rats. CHD‐FA (≥100 mg/kg p.o.) effectively reduced carrageenan‐induced paw edema in rats, which was comparable to 10 mg/kg p.o. indomethacin. Topical application of CHD‐FA, formulated to contain 1.75% active product in a cetomicrogol cream at pH 1.98, compared favorably with fusidic acid cream (10 mg/g) in accelerating the healing of excised wounds infected with Staphylococcus aureus. No signs of toxicity were observed in rats during the 6‐day acute and 6‐month chronic treatment with CHD‐FA (100 mg/kg p.o.). Topical application of CHD‐FA, formulated in UEA cream and applied to the right ears of mice at 400 mg/g body weight on days 1 and 7–38, produced no adverse events. No signs of toxicity were observed in the teratogenicity study, in which CHD‐FA was administered at 100 mg/kg p.o. to pregnant female mice 3 days before fertilization to 14 days of pregnancy. In conclusion, CHD‐FA is a safe compound with anti‐inflammatory and wound‐healing properties and merits further evaluation in the treatment of patients suffering from similar conditions. Drug Dev Res 73: 18–23, 2012. © 2011 Wiley Periodicals, Inc.
Generation and characterization of col10a1‐mcherry reporter mice
Authors: Maye Peter , Fu Yu , Butler David L. , Chokalingam Kumar , Liu Yaling , Floret Jane , Stover Mary Louise , Wenstrup Richard , Jiang Xi , Gooch Cindi , Rowe David
Published: June 2011

The fluorescent marking of immature (blue) and hypertrophic (red) chondrocytes in an E17.5 mouse embryo by the Collagen, type II, alpha 1 promoter driving the expression of enhanced cyan fluorescent protein (blue) and the Collagen, type X, alpha 1 BAC driving the expression of mCherry fluorescent protein (red), respectively. See the article by Maye et al. in this issue.
Habitat fragmentation and its effects on groundwater populations
Authors: Moldovan Oana Teodora , Meleg Ioana N. , Perşoiu Aurel
Published: June 2011

The subterranean unsaturated zone of the karstic areas is highly fragmented. The maze of more or less connected voids harbors simple communities of mixed surface and subterranean species, especially crustaceans. Hypogean species are dominant in almost all communities of the seven stations sampled monthly in a cave of the north‐western Romania. Water stable isotopes and drip rates were used to understand the morphological and spatial organization of the subterranean habitats in the unsaturated zone. The structure of the cave communities, the species synchrony and the spatial structure and variation of communities at different geographical levels are discussed in conservation terms. Copyright © 2011 John Wiley & Sons, Ltd.
The DNA methylome of benign and malignant parathyroid tumors
Authors: Starker Lee F. , Svedlund Jessica , Udelsman Robert , Dralle Henning , Åkerström Göran , Westin Gunnar , Lifton Richard P. , Björklund Peyman , Carling Tobias
Published: June 2011

The role of DNA methylation of CpG islands in parathyroid tumorigenesis has not been analyzed in an unbiased, systematic fashion. DNA was isolated from normal and pathologic parathyroid tissues, bisulphite modified and analyzed using the Infinium HumanMethylation27 BeadChip. Distinct hierarchical clustering of genes with altered DNA methylation profiles in normal and pathologic parathyroid tissue was evident. Comparing normal parathyroid tissue with parathyroid adenomas, 367 genes were significantly altered, while 175 genes significantly differed when comparing parathyroid carcinomas and normal parathyroid tissues. A comparison between parathyroid adenomas and parathyroid carcinomas identified 263 genes with significantly distinct methylation levels. Results were confirmed for certain genes in a validation cohort of 40 parathyroid adenomas by methylation‐specific PCR. Genes of known or putative importance in the development of parathyroid tumors showed significant and frequent hypermethylation. DNA hypermethylation of CDKN2B, CDKN2A, WT1, SFRP1, SFRP2, and SFRP4 was associated with reduced gene expression in both benign and malignant parathyroid tumors. Treatment with 5‐aza‐2′‐deoxycytidine of primary cell cultures restores expression of hypermethylated genes in benign and malignant parathyroid tumors. In conclusion, the unbiased, genome‐wide study of the parathyroid tumor DNA methylome identified a number of genes with altered DNA methylation patterns of putative importance to benign and malignant parathyroid tumorigenesis. © 2011 Wiley‐Liss, Inc.
Yielding elements – requirements, overview and comparison / Stauchelemente – Anforderungen, Überblick und Vergleich
Authors: Moritz Bernd
Published: June 2011

Large deformations are usual for tunnel excavation in weak rock mass and high overburden. In order to avoid overloading the support, various ductile support systems have been developed in the last 15 years to permit the controlled build‐up of load in the lining. The design of such a ductile support system requires the consideration of the development of displacements in space and time, the time‐dependent properties of the shotcrete and the characteristics of the ductile elements. The requirements for a yielding system are described. The latest developments in yielding elements for use with shotcrete support are discussed and their general performance and effectiveness are explained.

Bei Tunnelvortrieben in Gebirge geringer Qualität und hoher Überlagerung treten in der Regel große Verformungen auf. Zur Vermeidung einer Überbeanspruchung des Ausbaus wurden in den letzten 15 Jahren unterschiedliche duktile Ausbausysteme entwickelt, die einen kontrollierten Lastaufbau in der Auskleidung erlauben. Zur Auslegung eines solchen duktilen Ausbaus müssen die räumliche und zeitliche Entwicklung der Verschiebungen sowie die zeitabhängigen Eigenschaften des Spritzbetons und die Charakteristik der duktilen Elemente berücksichtigt werden. Die Anforderungen an ein nachgiebiges System werden dargelegt. Die jüngsten Entwicklungen von Stauchelementen in Zusammenhang mit Spritzbetonauskleidungen werden gezeigt und deren generelle Leistung und Wirksamkeit durchleuchtet.
The new Semmering base tunnel – tunnel design in the fault zone / Semmering‐Basistunnel neu – Tunneldesign in der Störungszone
Authors: Daller Josef , Atzl Georg , Weigl Johannes
Published: June 2011

During the design work for the permit application for the approximately 27.3 km long new Semmering Base Tunnel between Gloggnitz and Mürzzuschlag, it has become apparent that due to its extent, the section through the Graßberg‐Schlagl fault system will be more problematic than had been assumed during the route selection process. The article discusses the technical possibilities for the construction of the running tunnels through the fault zone. Support concepts with a second layer of shotcrete and short ring closure are investigated using numerical, timedependent calculations. The time dependence is influenced by the advance‐rate and the consolidation of the fault material. The determination of the rock characteristics for the core fault zone is based on triaxial compression tests.

Im Zuge der Einreichplanung für den rund 27, 3 km langen Semmering‐ Basistunnel neu zwischen Gloggnitz und Mürzzuschlag hat sich gezeigt, dass die Durchörterung des Graßberg‐Schlagl‐ Störungssystems aufgrund dessen Ausdehnung schwieriger wird, als im Trassenauswahlverfahren angenommen. Der Beitrag behandelt die technischen Möglichkeiten zur Herstellung der Streckenröhren im Störungsbereich. Dabei werden Ausbaukonzepte mit einer zweiten Spritzbetonschale und kurzem Ringschluss mittels numerischer zeitabhängiger Berechnungen untersucht. Die Zeitabhängigkeit wird durch die Vortriebsgeschwindigkeit und die Konsolidierung des Störungsmaterials beeinflusst. Die Ermittlung der Kennwerte für den Kern‐Störungsbereich erfolgt auf Basis von triaxialen Druckversuchen.
Are public health authorities able to “steer” rather than “row”? An empirical analysis in the Italian National Health Service
Authors: Longo Francesco , Salvatore Domenico , Tasselli Stefano
Published: June 2011

The nature of the local health authorities (LHAs) in the Italian National Health Service has been deeply reformed during the 1990s by new public management (NPM) reforms that introduced decentralization, quasi‐market and managerialism. These reforms implied that the main role of LHA is to govern the production of health services in their area (steer) rather than to only directly produce services (row). After more than 15 years from these reforms of Italian healthcare, we describe how much the steering versus rowing dichotomy made an impact on LHA activity, through an analysis of the management control systems they set up for themselves and the subsequent qualitative analysis of the opinions that a diverse group of managers expressed during 8 days of group discussion. Results show that managers of Italian LHAs, when only a small part of services is produced, tend to perceive their steering role as impossible to play and focus on production, leaving therefore ungoverned a significant part of the services offered to residents. NPM, therefore, was able to influence the reform of Italian healthcare but, as suggested by a postmodernist interpretation, left managers with a rhetoric change based on inconsistent assumptions instead of actionable ideas to manage the change process. Copyright © 2011 John Wiley & Sons, Ltd.
MicroRNA‐30a inhibits epithelial‐to‐mesenchymal transition by targeting Snai1 and is downregulated in non‐small cell lung cancer
Authors: Kumarswamy Regalla , Mudduluru Giridhar , Ceppi Paolo , Muppala Santoshi , Kozlowski Miroslaw , Niklinski Jacek , Papotti Mauro , Allgayer Heike
Published: June 2011

MicroRNAs (miRNAs) are small non‐coding RNAs which regulate gene expression by base‐pairing to the 3′‐UTR of the target mRNA. Recently, miRNAs have been shown to regulate cancer metastasis, however, central molecular mechanisms of this ability still need to be investigated. Epithelial to mesenchymal transition (EMT), which is characterized especially by repression of E‐cadherin expression and increased cell motility, is an essential component of cancer metastasis and progression. In the present study, we found that Snai1, a known transcriptional repressor of E‐cadherin and modulator of EMT, is post‐transcriptionally targeted by miRNA‐30a in non‐small cell lung cancer (NSCLC). Consistent with this, microRNA‐30a expression was found inversely proportional to the invasive potential of various NSCLC cell lines, correlating positively with E‐cadherin (epithelial marker) and negatively with N‐cadherin (mesenchymal marker) expression. Forced re‐introduction of miR‐30a significantly altered cell morphology, in vitro invasion and migration of invasive cell lines, this being paralleled by a downregulation of Snai1 and upregulation of E‐cadherin expression. Using a chicken embryonic metastasis assay, we found that miR‐30a suppresses in vivo distant metastasis to the lungs and liver. Finally, we screened the expression of miR‐30a in 64 consecutively resected NSCLC patients and found that, in 81% of the patients, expression of miR‐30a was downregulated significantly (p < 0.0001) in tumors compared to corresponding normal tissues. These results suggest that miR‐30a targets Snai1, inhibits invasion and metastasis, and is downregulated in NSCLC.
On the size distortion of tests after an overidentifying restrictions pretest
Authors: Guggenberger Patrik , Kumar Gitanjali
Published: June 2011

In the linear instrumental variables model, we provide theoretical and Monte Carlo evidence for the size distortion of a two‐stage hypothesis test that uses a test of overidentifying restrictions (OR) in the first stage. We derive a lower bound for the asymptotic size of the two‐stage test. The lower bound is given by the asymptotic size of a test that rejects the null hypothesis when two conditions are met: the test of OR used in the first stage does not reject and the test in the second stage rejects. This lower bound can be as large as 1 − εP, where εP is the pretest nominal size, for a parameter space that allows for local non‐exogeneity of the instruments but rules out weak instruments. Copyright © 2011 John Wiley & Sons, Ltd.
An essential role for the association of CD47 to SHPS-1 in skeletal remodeling
Authors: Maile Laura A , DeMambro Victoria E , Wai Christine , Aday Ariel W , Capps Byron E , Beamer Wesley G , Rosen Clifford J , Clemmons David R
Published: June 2011

Integrin-associated protein (IAP/CD47) has been implicated in macrophage-macrophage fusion. To understand the actions of CD47 on skeletal remodeling, we compared Cd47−/− mice with Cd47+/+ controls. Cd47−/− mice weighed less and had decreased areal bone mineral density compared with controls. Cd47−/− femurs were shorter in length with thinner cortices and exhibited lower trabecular bone volume owing to decreased trabecular number and thickness. Histomorphometry revealed reduced bone-formation and mineral apposition rates, accompanied by decreased osteoblast numbers. No differences in osteoclast number were observed despite a nonsignificant but 40% decrease in eroded surface/bone surface in Cd47−/− mice. In vitro, the number of functional osteoclasts formed by differentiating Cd47−/− bone marrow cells was significantly decreased compared with wild-type cultures and was associated with a decrease in bone-resorption capacity. Furthermore, by disrupting the CD47–SHPS-1 association, we found that osteoclastogenesis was markedly impaired. Assays for markers of osteoclast maturation suggested that the defect was at the point of fusion and not differentiation and was associated with a lack of SHPS-1 phosphorylation, SHP-1 phosphatase recruitment, and subsequent dephosphorylation of non–muscle cell myosin IIA. We also demonstrated a significant decrease in osteoblastogenesis in bone marrow stromal cells derived from Cd47−/− mice. Our finding of cell-autonomous defects in Cd47−/− osteoblast and osteoclast differentiation coupled with the pronounced skeletal phenotype of Cd47−/− mice support the conclusion that CD47 plays an important role in regulating skeletal acquisition and maintenance through its actions on both bone formation and bone resorption. © 2011 American Society for Bone and Mineral Research
Construct drift in the MMPI‐2 restructured clinical scales: further evidence and a possible historic example
Authors: Kevin Bolinskey P. , Nichols David S.
Published: June 2011

Construct drift (Nichols, 2006) describes the possibility that the MMPI‐2 Reconstructed Clinical (RC) scales are less accurate measures of the primary traits than the original Clinical scales. The authors review the development of RC scales RC4, RC7, and RC9 and provide further evidence that these scales measure traits and behaviors that are not necessarily equivalent to those assessed by the original scales. Further, the development of the original Clinical Scale 7 is reviewed and evidence is provided that suggests that construct drift is not a new phenomenon, but may have been present in the development of the original scales. Suggestions for future research as well as cautions with regard to the clinical interpretation of the RC scales are provided. © 2011 Wiley Periodicals, Inc. J Clin Psychol 67:1–11, 2011.
CID of singly charged antioxidants applied in lubricants by means of a 3D ion trap and a linear ion trap–Orbitrap mass spectrometer
Authors: Kassler Alexander , Pittenauer Ernst , Doerr Nicole , Allmaier Guenter
Published: June 2011

The aim of this study was to investigate the fragmentation behavior induced by low‐energy collision‐induced dissociation (LE‐CID) of four selected antioxidants applied in lubricants, by two different types of ion trap mass spectrometers: a three‐dimensional ion trap (3D‐IT) and a linear IT (LIT) Orbitrap MS. Two sterically hindered phenols and two aromatic amines were selected as model compounds representing different antioxidant classes and were characterized by positive‐ion electrospray ionization (ESI) and LE‐CID. Various types of molecular ions (e.g. [M]+•, [M + H]+, [M + NH4]+ or [M + Na]+) were used as precursor ions generating a significant number of structurally relevant product ions. Furthermore, the phenolic compounds were analyzed by negative‐ion ESI. For both IT types applied for fragmentation, the antioxidants exhibited the same unusual LE‐CID behavior: (1) they formed stable radical product ions and (2) CC bond cleavages of aliphatic substituents were observed and their respective cleavage sites depended on the precursor ion selected. This fragmentation provided information on the type of structural isomer usually not obtainable for branched aliphatic substituents utilizing LE‐CID. Comparing the two instruments, the main benefit of applying the LIT‐Orbitrap was direct access to elemental composition of product ions enabling unambiguous interpretation of fragmentation trees not obtainable by the 3D‐IT device (e.g. loss of isobaric neutrals). It should be emphasized that the types of product ions formed do not depend on the type of IT analyzer applied. For characterizing degradation products of antioxidants, the LIT‐Orbitrap hybrid system, allowing the determination of accurate m/z values for product ions, is the method of choice. Copyright © 2011 John Wiley & Sons, Ltd.
Proton transfer reactions for improved peptide characterisation
Authors: Rožman Marko , Schneider Andrea , Gaskell Simon J.
Published: June 2011

The combination of deprotonation (via ion/molecule and ion/ion reactions) and low‐energy collision‐induced dissociation (CID) has been explored for the enhanced characterisation of tryptic peptides via access to different precursor charge states. This approach allows instant access to fragmentation properties of singly and doubly protonated precursors (arising from the availability of mobile protons) in a single experiment. Considering both charge states extended our base of structurally informative data (in comparison with considering just a single charge state) due to generation of additional sequence ions and by obtaining supplementary structural information derived from selective cleavages. Roughly 37% of combined data sets (CID spectra of doubly and singly charged precursor) showed a greater database identification confidence than each set alone. Moreover, comparison between a number of sequence ions of the singly charged precursor and the doubly charged precursor provided a mean of distinguishing the two classes of tryptic peptides (arginine or lysine containing). Copyright © 2011 John Wiley & Sons, Ltd.
It is time for a paradigm shift in drug discovery bioanalysis: from SRM to HRMS
Authors: Ramanathan Ragu , Jemal Mohammed , Ramagiri Suma , Xia Yuan‐Qing , Humpreys W. Griffith , Olah Timothy , Korfmacher Walter A.
Published: June 2011

It can be argued that the last true paradigm shift in the bioanalytical (BA) arena was the shift from high‐performance liquid chromatography (HPLC) with ultraviolet (UV) detection to HPLC with tandem mass spectrometry (MS/MS) detection after the commercialization of the triple quadrupole mass spectrometer in the 1990s. HPLC‐MS/MS analysis based on selected reaction monitoring (SRM) has become the gold standard for BA assays and is used by all the major pharmaceutical companies for the quantitative analysis of new drug entities (NCEs) as part of the new drug discovery and development process. While LC‐MS/MS continues to be the best tool for drug discovery bioanalysis, a new paradigm involving high‐resolution mass spectrometry (HRMS) and ultrahigh‐pressure liquid chromatography (uHPLC) is starting to make inroads into the pharmaceutical industry. The ability to collect full scan spectra, with excellent mass accuracy, mass resolution, 10–250 ms scan speeds and no NCE‐related MS parameter optimization, makes the uHPLC‐HRMS techniques suitable for quantitative analysis of NCEs while preserving maximum qualitative information about other drug‐related and endogenous components such as metabolites, degradants, biomarkers and formulation materials. In this perspective article, we provide some insight into the evolution of the hybrid quadrupole‐time‐of‐flight (Qq‐TOF) mass spectrometer and propose some of the desirable specifications that such HRMS systems should have to be integrated into the drug discovery bioanalytical workflow for performing integrated qualitative and quantitative bioanalysis of drugs and related components. Copyright © 2011 John Wiley & Sons, Ltd.