bluuebunny/crossref_metadata_2025 huggingface dataset:
Bifurcated Forced Convective Heat Transfer of Supercritical CO2 Flow in Plane Symmetric Sudden Expansion Duct
Authors: Deng Bi-Li , Zhang Xin-Rong , Yamaguchi Hiroshi
Published: November 2010

This study presents a computational investigation of forced convection of supercritical CO2 flow in plane symmetric sudden expansion duct at an expansion ratio of 2 in flow asymmetric regime. Computations were conducted at various Reynolds numbers in flow asymmetric regime and low wall heat fluxes below 500 W/m2 to examine the Reynolds number and thermal effects on the flow and heat transfer of the bifurcated flow. General flow features and temperature distributions are presented. The transitional Reynolds numbers above, which a third recirculation region will appear at different wall heat flux are presented, and thus thermal effects on the flow stability are discussed. Reynolds number and thermal effects on distributions of wall skin friction, pressure coefficient, and Nusselt number are presented and discussed.
Heat Transfer in Thin Multilayered Plates—Part II: Applications to the Composite Patch Repair Technique
Authors: Papathanasiou T. K. , Markolefas S. I. , Filopoulos S. P. , Tsamasphyros G. J.
Published: November 2010

This second part of our contribution entitled, “Heat Transfer in Thin Multilayered Plates,” refers to the modeling of an advanced repair technique, known as the composite patch repair (CPR). Thermal analysis of this particular application is highly complicated due to the geometry of the domains and the fact that many different materials participate in the implementation. In this paper, we take advantage of the fact that both the composite patch and the damaged plate to be repaired are of very small thickness. In that way, the whole domain may be treated as a thin multilayer area of extended surface. These properties make the thermal analysis of CPR an ideal field for using the method presented in the previous part of our analysis.
Patient-Specific Modeling of Corneal Refractive Surgery Outcomes and Inverse Estimation of Elastic Property Changes
Authors: Roy Abhijit Sinha , Dupps William J.
Published: November 2010

The purpose of this study is to develop a 3D patient-specific finite element model (FEM) of the cornea and sclera to compare predicted and in vivo refractive outcomes and to estimate the corneal elastic property changes associated with each procedure. Both eyes of a patient who underwent laser-assisted in situ keratomileusis (LASIK) for myopic astigmatism were modeled. Pre- and postoperative Scheimpflug anterior and posterior corneal elevation maps were imported into a 3D corneo-scleral FEM with an unrestrained limbus. Preoperative corneal hyperelastic properties were chosen to account for meridional anisotropy. Inverse FEM was used to determine the undeformed corneal state that produced <0.1% error in anterior elevation between simulated and in vivo preoperative geometries. Case-specific 3D aspheric ablation profiles were simulated, and corneal topography and spherical aberration were compared at clinical intraocular pressure. The magnitude of elastic weakening of the residual corneal bed required to maximize the agreement with clinical axial power was calculated and compared with the changes in ocular response analyzer (ORA) measurements. The models produced curvature maps and spherical aberrations equivalent to in vivo measurements. For the preoperative property values used in this study, predicted elastic weakening with LASIK was as high as 55% for a radially uniform model of residual corneal weakening and 65% at the point of maximum ablation in a spatially varying model of weakening. Reductions in ORA variables were also observed. A patient-specific FEM of corneal refractive surgery is presented, which allows the estimation of surgically induced changes in corneal elastic properties. Significant elastic weakening after LASIK was required to replicate clinical topographic outcomes in this two-eye pilot study.
Computational Fluid Dynamics Simulations of Particle Deposition in Large-Scale, Multigenerational Lung Models
Authors: Walters D. Keith , Luke William H.
Published: November 2010

Computational fluid dynamics (CFD) has emerged as a useful tool for the prediction of airflow and particle transport within the human lung airway. Several published studies have demonstrated the use of Eulerian finite-volume CFD simulations coupled with Lagrangian particle tracking methods to determine local and regional particle deposition rates in small subsections of the bronchopulmonary tree. However, the simulation of particle transport and deposition in large-scale models encompassing more than a few generations is less common, due in part to the sheer size and complexity of the human lung airway. Highly resolved, fully coupled flowfield solution and particle tracking in the entire lung, for example, is currently an intractable problem and will remain so for the foreseeable future. This paper adopts a previously reported methodology for simulating large-scale regions of the lung airway (Walters, D. K., and Luke, W. H., 2010, “A Method for Three-Dimensional Navier–Stokes Simulations of Large-Scale Regions of the Human Lung Airway,” ASME J. Fluids Eng., 132(5), p. 051101), which was shown to produce results similar to fully resolved geometries using approximate, reduced geometry models. The methodology is extended here to particle transport and deposition simulations. Lagrangian particle tracking simulations are performed in combination with Eulerian simulations of the airflow in an idealized representation of the human lung airway tree. Results using the reduced models are compared with those using the fully resolved models for an eight-generation region of the conducting zone. The agreement between fully resolved and reduced geometry simulations indicates that the new method can provide an accurate alternative for large-scale CFD simulations while potentially reducing the computational cost of these simulations by several orders of magnitude.
Biomechanical Measurements of Torsion-Tension Coupling in Human Cadaveric Femurs
Authors: Zdero Rad , McConnell Alison J. , Peskun Christopher , Syed Khalid A. , Schemitsch Emil H.
Published: November 2010

The mechanical behavior of human femurs has been described in the literature with regard to torsion and tension but only as independent measurements. However, in this study, human femurs were subjected to torsion to determine if a simultaneous axial tensile load was generated. Fresh frozen human femurs (n=25) were harvested and stripped of soft tissue. Each femur was mounted rigidly in a specially designed test jig and remained at a fixed axial length during all experiments. Femurs were subjected to external and internal rotation applied at a constant angulation rate of 0.1 deg/s to a maximum torque of 12 N m. Applied torque and generated axial tension were monitored simultaneously. Outcome measurements were extracted from torsion-versus-tension graphs. There was a strong relationship between applied torsion and the resulting tension for external rotation tests (torsion/tension ratio=551.7±283.8 mm, R2=0.83±0.20, n=25), internal rotation tests (torsion/tension ratio=495.3±233.1 mm, R2=0.87±0.17, n=24), left femurs (torsion/tension ratio=542.2±262.4 mm, R2=0.88±0.13, n=24), and right femurs (torsion/tension ratio=506.7±260.0 mm, R2=0.82±0.22, n=25). No statistically significant differences were found for external versus internal rotation groups or for left versus right femurs when comparing torsion/tension ratios (p=0.85) or R2 values (p=0.54). A strongly coupled linear relationship between torsion and tension for human femurs was exhibited. This suggests an interplay between these two factors during activities of daily living and injury processes.
Si single electron transistor fabricated by chemical mechanical polishing
Authors: Lee Yen-Chun , Joshi Vishwanath , Orlov Alexei O. , Snider Gregory L.
Published: November 2010

The authors report the results of a novel single electron transistor (SET) fabrication technique that combines the unique advantages of chemical mechanical polishing and the versatility and scalability of silicon processing. A thin (∼15 nm) line of degenerately doped silicon on insulator is embedded in a planarized plasma enhanced chemical vapor deposition oxide through nanoencapsulation. A pit in this line is formed by a highly selective silicon dry etch, and the tunnel oxide is grown on the sidewalls of the pit using rapid thermal oxidation. Degenerately doped amorphous silicon is deposited into the pit to form the SET island, the overburden of silicon is removed, and the structure is thinned down by chemical mechanical polishing. The SET’s charging diagram indicates a charging energy of around 20 meV, credited to its small tunnel junction size as well as possible “puddle” formation from the dopant distribution within the island and the leads. The observed anomalies, such as missing and split diamonds in the charging plots and random telegraph signals, suggest that the donor sites play an important role in the device operation. Several fabricated SETs show a similar Coulomb blockade at 4 K, demonstrating reasonable yield for the process.
Application of analytic scanning electron microscopy to critical dimensions metrology at nanometer scale
Authors: Babin Sergey , Bay Konstantin , Hwu Justin J.
Published: November 2010

Scanning electron microscopy (SEM) metrology involves significant uncertainty of the linewidth measurement because the SEM image brightness is a complex function of SEM setup, pattern materials, and shape. In this work, the authors used an analytical SEM for critical dimensions metrology applications on a quartz nanoimprint template. The SEM was tuned to find the best condition for consistent operation. Beam characterization was done using BEAMETR beam measurement technique. SEM images of templates were taken at optimum conditions. The measurements were done using two methods: regular imaging processing software based on brightness threshold and using physical model based processing tool myCD. The quartz template was then measured using transmission electron microscopy cross sections at selected sites to reveal profile information as metrology comparison reference. The metrology capability and limitations of analytical SEM with regular image processing were identified. The considerable improvement of accuracy using the physics based image processing was found.
Platinum single-electron transistors with tunnel barriers made by atomic layer deposition
Authors: George Hubert C. , Orlov Alexei O. , Snider Gregory L.
Published: November 2010

The fabrication and measurements of platinum single-electron transistors (SETs) employing high quality insulating barriers produced by atomic layer deposition (ALD) of alumina (Al2O3) are reported. The G-Vds, Coulomb blockade oscillations, and the charging diagram of the SET at 300 mK were successfully measured. The ALD technique provides atomic accuracy and precise control of the tunnel barriers and greatly expands the choice of materials suitable for SET fabrication (both electrodes and island materials as well as barrier dielectrics). This fabrication method is targeted toward large scale production of SETs, which will accelerate their adoption into practical applications.
Micro-Optical Sectioning Tomography to Obtain a High-Resolution Atlas of the Mouse Brain
Authors: Li Anan , Gong Hui , Zhang Bin , Wang Qingdi , Yan Cheng , Wu Jingpeng , Liu Qian , Zeng Shaoqun , Luo Qingming
Published: November 2010

Better Brain Maps

A high-resolution atlas of the complete neuronal connectivity in a whole brain should fundamentally advance our understanding of the organization and function of animal nervous systems. Now,

A. Li.
et al.

(p.
1404
, published online 4 November) describe an automated system, micro-optical sectioning tomography, that allowed three-dimensional mapping of the morphology and spatial location of neurons and traces of neurites in a whole, intact mouse brain.
Frequent Mutation of
BAP1
in Metastasizing Uveal Melanomas
Authors: Harbour J. William , Onken Michael D. , Roberson Elisha D. O. , Duan Shenghui , Cao Li , Worley Lori A. , Council M. Laurin , Matatall Katie A. , Helms Cynthia , Bowcock Anne M.
Published: November 2010

An Eye on Metastasis

Despite the considerable progress being made in elucidating the cell biology of metastasis, little is known about the genetic alterations that promote metastasis of human tumors, the cause of most cancer deaths. A potentially important clue now emerges from the work of

Harbour
et al.

(p.
1410
, published online 4 November), who used an exome-sequencing approach to search for genetic mutations in uveal melanomas, an eye cancer associated with a high rate of fatal metastasis. Remarkably, over 80% of tumor samples with a high metastatic risk had inactivating somatic mutations in the gene encoding BAP1 (BRCA1-associated protein 1), a nuclear protein involved in controlling protein degradation. Thus, in this tumor type, mutational inactivation of BAP1 may be a key event in the acquisition of metastatic competence.
The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation
Authors:   The International HIV Controllers Study
Published: November 2010

Getting HIV Under Control

Approximately 1 in 300 people infected with HIV are HIV “controllers” who are able to maintain long-term control of the virus without medication and who do not progress to AIDS. Uncovering the genetic basis for this ability is of great interest.

Pereyra
et al.

(p.
1551
, published online 4 November; see the Perspective by

McMichael and Jones

) now present genome-wide association results from patients enrolled in the International HIV Controllers Study. The analysis compared HIV controllers of European, African-American, and Hispanic descent with HIV progressors and found >300 variants that reached genome-wide significance, all of which were in the major histocompatibility class I (HLA) region on chromosome 6. Analysis of the effects of individual amino acids within classical HLA proteins revealed six independently significant residues, five of which lined the peptide-binding groove. Thus, differences in binding to viral peptide antigens by HLA may be the major factors underlying genetic differences between HIV controllers and progressors.
Toroidal Dipolar Response in a Metamaterial
Authors: Kaelberer T. , Fedotov V. A. , Papasimakis N. , Tsai D. P. , Zheludev N. I.
Published: November 2010

Making a Point with Metamaterials

A long-predicted electromagnetic excitation, the toroidal moment (or anapole), is associated with toroidal shape and current flow within a structure and has been implicated in nuclear and particle physics. This distinct family of electromagnetic excitations has not been observed directly because they are masked by much stronger electric and magnetic multipoles.

Kaelberer
et al.

(p.
1510
, published online 4 November) have developed a metamaterial structure based on stacked loops of inverted split-ring resonators (“metamolecules”) whose response under excitation is consistent with the existence of a toroidal moment. The metamaterial is designed so that both the electric and magnetic dipole moments induced by an incident electromagnetic wave are suppressed, while the toroidal response is isolated and resonantly enhanced to a detectable level.
Thirteen‐week dose‐intensifying simultaneous combination chemotherapy protocol for malignant lymphoma in dogs
Authors: Zenker I. , Meichner K. , Steinle K. , Kessler M. , Hirschberger J.
Published: November 2010

This prospective study aimed to record the toxicity profile of a dose‐intensifying simultaneous chemotherapy (DISC) protocol for lymphoma in dogs. Remission rates and the duration of the protocol were also evaluated. Twenty‐one dogs were studied. Diagnosis was based on cytological or histological assessments. The DISC protocol is a 13‐week maintenance‐free protocol. L‐Asparaginase (400 iu/kg) was administered subcutaneously on day 1, followed by weekly simultaneous intravenous administration of vincristine (0.7 mg/m2= 100 per cent), cyclophosphamide (200 mg/m2= 100 per cent) and doxorubicin (30 mg/m2= 100 per cent) at a starting dose level of 33 per cent. Dose levels were given twice and then increased by 5 to 7 per cent if grade 0 or I toxicities were seen, to a maximum dose level of 60 per cent. Two dogs experienced a grade IV toxicity (asymptomatic neutropenia in one dog and sepsis in the other). Two episodes of asymptomatic grade III thrombocytopenia and one episode of neutropenia were recorded. Other toxic events were infrequent and mild. Only one dog required hospitalisation for less than 72 hours. Seventeen dogs (80.9 per cent) achieved complete remission, one (4.8 per cent) achieved partial remission, two (9.5 per cent) had stable disease and in one (4.8 per cent) disease progressed.
Owners' observations of domestic cats after limb amputation
Authors: Forster L. M. , Wathes C. M. , Bessant C. , Corr S. A.
Published: November 2010

Questionnaires were distributed to owners of cats that had undergone limb amputation in the UK, through 1000 veterinary clinics or publications relating to companion cats, or online. Between July 2009 and February 2010, responses were received relating to 234 cats, and data for 204 of these were included in subsequent analyses. The responses received provided data on signalment, aetiology, quality of life, behavioural changes and pain observed in cats after partial or total amputation of a limb. Young male domestic shorthair cats were over‐represented in the sample; the most common reason for amputation was a fractured bone, and the hindlimb was almost twice as likely to be amputated as the forelimb. Although 89 per cent of the cats received analgesics/anti‐inflammatories after discharge, the owners of 35 per cent of the animals observed some signs of pain during recovery. Eighty‐nine per cent of the cats were thought to have regained a ‘normal’ quality of life as defined by the owner and 94 per cent of the owners stated that they would agree with the decision to amputate the affected limb in a pet if faced with the same decision again.
Ring-chain equilibria of R-but-3-enoate esters — A quantum mechanical study of direct and indirect ring-closing reactions
Authors: Burt Michael B. , Crane Angela K. , Su Ning , Rice Nicole , Poirier Raymond A.
Published: November 2010

Macrocyclic structures can be synthesized through two simultaneous olefin metathesis reactions: either directly through ring-closing metathesis (RCM) or indirectly through an intermediate formed by acyclic diene metathesis (ADMET). The proclivity of a homologous series of 16 R-but-3-enoate esters to form lactones through one of these two processes is studied at the HF/6–31G(d), B3LYP/6–31G(d), and MP2(full)/6–31G(d) levels of theory. Computed Gibbs free energies are used to determine ΔGRCM, ΔGADMET, and ΔΔG (ΔGRCM – ΔGADMET). ΔΔG is evaluated to compare the relative favourability of the RCM and ADMET reactions for the various R-but-3-enoate esters, where each system is differentiated by the number of methylene groups (n) added to the ester chain. When n = 0, 1, 10, or 13, cyclic lactone formation by direct RCM is predicted to be thermodynamically favoured, and the indirect synthesis is preferred for all other heterocyclic structures. The same trend holds between 298.15 and 333.15 K, therefore, the gas-phase model is a reasonable approximation of the experimental reaction conditions. The theoretical model is sufficient for smaller systems, but molecules larger than the n = 6 case do not follow experimental results for similar saturated structures. Hence, the assumptions pertaining to straight-chain and cis-ring conformations need to be re-evaluated. In particular, chain flexibility should be further examined.
A computational study of the threshold energies of the 1,2-FCl interchange reaction of chlorofluoroethanes
Authors: Everett William C. , Holmes Bert E. , Heard George L.
Published: November 2010

The 1,2-FCl rearrangement reaction of a series of haloethanes is investigated by comparisons of the optimized ground- and transition-state geometries. Investigation of the effect of level of theory and basis set shows that the trends in threshold energies for rearrangement are reproduced across all levels of theory and basis set, and hence that a moderate level of theory and basis set is adequate for investigating the important trends in this reaction. Threshold barriers increase when a large number of fluorine atoms are attached to the carbon atom bearing the interchanging fluorine, suggesting that the C–F bonds prove difficult to distort to the transition geometry; the increase is smaller for fluorine substitution on the carbon atom bearing the interchanging hydrogen atom. By considering sets of isomeric reactions, the barrier height is shown to closely follow the thermodynamic stability of the alkane undergoing rearrangement; however there is a secondary effect owing to the relative stability of the transition geometry. This relative stability can be related to the thermodynamic stability of a series of isomeric alkenes that resemble the transition geometry without the rearranging atoms. This series of molecules constitute an unusual set owing to the ability to consider these three contributions to the activation barrier separately.
On the stabilization of the carbonate dianion by sulfur dioxide
Authors: Grein Friedrich , Chan Justin K. , Liko Idlir
Published: November 2010

The stabilization in the gas phase of the carbonate dianion [Formula: see text] by SO2 molecules is being investigated. The geometries of various isomers of [Formula: see text] (SO2)n and [Formula: see text] (SO2)n, for n = 1–4, have been optimized by the B3PW91/6−311+G(3df) method. Single-point CCSD and CCSD(T) energies at the DFT-optimized geometries were obtained for n = 1–3, using the 6−311+G(d) basis set. For n = 1 and 2, the monoanionic clusters are adiabatically more stable than the dianionic ones. However, starting at n = 3, they become less stable. The CCSD adiabatic electron detachment energy of the dianionic cluster switches from −0.39 eV for n = 2 to +0.20 eV for n = 3. The vertical electron detachment energy turns positive at n = 2, with a CCSD value of 1.35 eV. Several of the less stable dianionic, and most of the monoionic clusters, are characterized by the transfer of an oxygen atom from CO3 to SO2, forming [Formula: see text] or [Formula: see text] units, owing to [Formula: see text] + CO2 being more stable than [Formula: see text] + SO2. For the stabilization of the sulfate dianion by stepwise hydration, studied both experimentally and theoretically by other groups, a minimum of three water molecules was required.
A general measure of conjugation in biphenyls and their radical cations
Authors: Zhang Lei , Peslherbe Gilles H. , Muchall Heidi M.
Published: November 2010

Changes in the amount of conjugation in the biphenyl system upon torsion have been investigated with quantum chemistry computations. For the unsubstituted biphenyl and its radical cation, the change in the energy for the first electronic transition as determined from time-dependent density functional theory, specifically TD-B3LYP, upon an imposed change in torsion angle appears to provide a good general measure of the delocalization of the π-electrons. Upon substitution, though, a relationship could not be established between the excitation energy and the twist across the C–C bond connecting the two phenyl rings. In contrast, the π-interaction energy, i.e., the π–π interaction across the central C–C bond, determined from a natural bond orbital analysis, provides a uniform description of conjugation in the electronically different systems, for an imposed twist as well as upon substitution. Substituent effects are found to be larger and more varied for the biphenyl radical cations. Of particular interest is the introduction of the oxidizable substituents OCH3(methoxyl) and SCH3(methylthio), as this leads to the smallest changes in torsion angle in the biphenyl unit upon removal of an electron from the molecule. The findings of this work could ultimately prove useful for the rational design of conductive polymer materials.
The 9-barbaralyl and related C9H9+ carbocations — A QTAIM-DI-VISAB computational study
Authors: Werstiuk Nick H.
Published: November 2010

QTAIM-DI-VISAB analyses were used to characterize the bonding of the 9-barbaralyl cation, related C9H9+ cations, and rearrangement transition states. These analyses involved obtaining quantum theory of an atom in a molecule (QTAIM) molecular graphs and delocalization indexes (DIs) that were correlated with visualization of the proximities of atomic basins (VISAB). This study provides new insights into the bonding of these species and cements the QTAIM-DI-VISAB analysis as a method of choice for establishing the nature of the bonding in so-called nonclassical carbocations, while obviating the need for dashed-line representations of bonding.
Low-Voltage Oxide Homojunction Electric-Double-Layer Transistors Gated by Ion-Incorporated Inorganic Solid Electrolytes
Authors: Dou Wei , Sun Jia , Jiang Jie , Lu Aixia , Wan Qing
Published: November 2010

Porous inorganic dielectrics provide nanochannels for ion transportation, which is favorable for electric-double-layer (EDL) formation. 1% CaCl2-treated porous SiO2 shows an increased EDL specific capacitance of ∼4.2 µF/cm2. Low-voltage (1.0 V) indium–tin-oxide-based homojunction transistors gated by such a composite solid electrolyte are fabricated and characterized. After aging for one month in air ambient without surface passivation, such a device shows an equivalent field-effect mobility of 13 cm2 V-1 s-1, a current on/off ratio of 1.0×106, and a subthreshold swing of 80 mV/decade. Control experiment results demonstrate that the CaCl2 treatment can improve the stability of the EDL transistors.
Modification of Symmetric H State Lifetime in Splayed Nematic Cells
Authors: Huang Chi-Yen , Lai Po-chung , Hsieh Chia-Ting , Chang Che-Wei , Tian Ching-Jui
Published: November 2010

We investigate the transformation processes of splayed nematic cells. Experimental results reveal that polymer networks modify the lifetime of the symmetric H (Hs) state of splay nematic cells. Polymer networks that polymerize with voltage application suppress the lifetime of the Hs state, speeding up the formation of the Ha state. In contrast, polymer networks that polymerize without voltage application markedly enhance the lifetime of the Hs state. Under a 7 V bias voltage, the lifetime of the Hs state in a polymer-stabilized splayed nematic cell is ∼600 ms, which is ∼4 times that in a pristine splayed nematic cell.
Enhancement and Stabilization of Hole Concentration of Hydrogen-Terminated Diamond Surface Using Ozone Adsorbates
Authors: Kubovic Michal , Kasu Makoto
Published: November 2010

The p-type conductivity of H-terminated diamond surface can be linked to adsorption of a specific gas species on the surface. O3, NO2, NO, and SO2 were identified as adsorbates, which induce holes on the H-terminated diamond surface. Among them, exposure to O3 increases hole concentration the most. The O3-increased concentration remains high even after exposure to the gas has stopped, indicating that ozone is the most stable adsorbent. X-ray photospectroscopy spectra of O3-adsorbed H-terminated diamond surface show partial oxidation of the surface and upward band bending and are very similar to those of NO2 exposed diamond surfaces.
Effects of Hypergravity on Formation of Microporous Films by Dissipative Processes
Authors: Yabu Hiroshi , Hirai Yuji , Shimomura Masatsugu , Natsuisaka Makoto , Tsujii Kaoru
Published: November 2010

Microporous polymer films can be prepared by casting a solution of hydrophobic polymer and amphiphilic polymer on a solid substrate using condensed water droplet arrays as templates. Bacause of the temperature nonuniformity of the solution surface owing to thermal convections, water condenses heterogeneously. The heterogeneous condensation of water droplets induces the formation of irregular-size and -arrangement microporous film. To evaluate the effect of gravity on microporous film formation, we have successfully prepared the test chamber for hypergravity experiments. From the hypergravity experiment, the thermal convection during solvent evaporation was forced to be enhanced under hypergravity. As a result, the microporous structure was not observed under hypergravity. These results provided insight on water-assisted microporous film formation. Furthermore, the results strongly suggested that the microgravity enviroment is suitable for uniform and well-organized microporous film formation.
In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice
Authors: Takaishi Shigeo , Shibata Wataru , Tomita Hiroyuki , Jin Guangchun , Yang Xiangdong , Ericksen Russell , Dubeykovskaya Zinaida , Asfaha Samuel , Quante Michael , Betz Kelly S. , Shulkes Arthur , Wang Timothy C.
Published: November 2010

Gastrin is secreted from a subset of neuroendocrine cells residing in the gastric antrum known as G cells, but low levels are also expressed in fetal pancreas and intestine and in many solid malignancies. Although past studies have suggested that antral gastrin is transcriptionally regulated by inflammation, gastric pH, somatostatin, and neoplastic transformation, the transcriptional regulation of gastrin has not previously been demonstrated in vivo. Here, we describe the creation of an enhanced green fluorescent protein reporter (mGAS-EGFP) mouse using a bacterial artificial chromosome that contains the entire mouse gastrin gene. Three founder lines expressed GFP signals in the gastric antrum and the transitional zone to the corpus. In addition, GFP(+) cells could be detected in the fetal pancreatic islets and small intestinal villi, but not in these organs of the adult mice. The administration of acid-suppressive reagents such as proton pump inhibitor omeprazole and gastrin/CCK-2 receptor antagonist YF476 significantly increased GFP signal intensity and GFP(+) cell numbers in the antrum, whereas these parameters were decreased by overnight fasting, octreotide (long-lasting somatostatin ortholog) infusion, and Helicobacter felis infection. GFP(+) cells were also detected in the anterior lobe of the pituitary gland and importantly in the colonic tumor cells induced by administration with azoxymethane and dextran sulfate sodium salt. This transgenic mouse provides a useful tool to study the regulation of mouse gastrin gene in vivo, thus contributing to our understanding of the mechanisms involved in transcriptional control of the gastrin gene.
Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease
Authors: Ronis Martin J. J. , Hennings Leah , Stewart Ben , Basnakian Alexei G. , Apostolov Eugene O. , Albano Emanuele , Badger Thomas M. , Petersen Dennis R.
Published: November 2010

Male Sprague-Dawley rats were chronically fed a high-unsaturated-fat diet for 130 days by using total enteral nutrition (TEN), or the same diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g·kg−1·day−1. Relative to an ad libitum chow-fed group, the high-fat-fed controls had three- to fourfold greater expression of fatty acid transporter CD36 mRNA and developed mild steatosis but little other hepatic pathology. NAC treatment resulted in increased somatic growth relative to controls (4.0 ± 0.1 vs. 3.1 ± 0.1 g/day) and increased hepatic steatosis score (3.5 ± 0.6 vs. 2.7 ± 1.2), associated with suppression of the triglyceride hydrolyzing protein adiponutrin, but produced no elevation in serum alanine aminotransferase (ALT). Chronic EtOH treatment increased expression of fatty acid transport protein FATP-2 mRNA twofold, resulting in marked hepatic steatosis, oxidative stress, and a twofold elevation in serum ALT. However, no changes in tumor necrosis factor-α or transforming growth factor-β expression were observed. Fibrosis, as measured by Masson's trichrome and picrosirius red staining, and a twofold increase in expression of type I and type III collagen mRNA, was only observed after EtOH treatment. Long-term EtOH treatment increased hepatocyte proliferation but did not modify the hepatic mRNAs for hedgehog pathway ligands or target genes or genes regulating epithelial-to-mesenchymal transition. Although the effects of NAC on EtOH-induced fibrosis could not be fully evaluated, NAC had additive effects on hepatocyte proliferation and prevented EtOH-induced oxidative stress and necrosis, despite a failure to reverse hepatic steatosis.
Multiple splicing defects caused by hERG splice site mutation 2592+1G>A associated with long QT syndrome
Authors: Stump Matthew R. , Gong Qiuming , Zhou Zhengfeng
Published: November 2010

Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene ( hERG). Cryptic splice site activation in hERG has recently been identified as a novel pathogenic mechanism of LQT2. In this report, we characterize a hERG splice site mutation, 2592+1G>A, which occurs at the 5′ splice site of intron 10. Reverse transcription-PCR analyses using hERG minigenes transfected into human embryonic kidney-293 cells and HL-1 cardiomyocytes revealed that the 2592+1G>A mutation disrupted normal splicing and caused multiple splicing defects: the activation of cryptic splice sites within exon 10 and intron 10 and complete intron 10 retention. We performed functional and biochemical analyses of the major splice product, hERGΔ24, in which 24 amino acids within the cyclic nucleotide binding domain of the hERG channel COOH-terminus is deleted. Patch-clamp experiments revealed that the splice mutant did not generate hERG current. Western blot and immunostaining studies showed that mutant channels did not traffic to the cell surface. Coexpression of wild-type hERG and hERGΔ24 resulted in significant dominant-negative suppression of hERG current via the intracellular retention of the wild-type channels. Our results demonstrate that 2592+1G>A causes multiple splicing defects, consistent with the pathogenic mechanisms of long QT syndrome.
Ventilatory and carotid body chemoreceptor responses to purinergic P2X receptor antagonists in newborn rats
Authors: Niane Lalah M. , Donnelly David F. , Joseph Vincent , Bairam Aida
Published: November 2010

Adenosine triphosphate, acting through purinergic P2X receptors, has been shown to stimulate ventilation and increase carotid body chemoreceptor activity in adult rats. However, its role during postnatal development of the ventilatory response to hypoxia is yet unknown. Using whole body plethysmography, we measured ventilation in normoxia and in moderate hypoxia (12% fraction of inspired O2, 20 min) before and after intraperitoneal injection of suramin (P2X2 and P2X3 receptor antagonist, 40 mg/kg) in 4-, 7-, 12-, and 21-day-old rats. Suramin reduced baseline breathing (∼20%) and the response to hypoxia (∼30%) in all rats, with a relatively constant effect across ages. We then tested the effect of the specific P2X3 antagonist, A-317491 (150 mg/kg), in rats aged 4, 7, and 21 days. As with suramin, A-317491 reduced baseline ventilation (∼55%) and the hypoxic response (∼40%) at all ages studied. Single-unit carotid body chemoreceptor activity was recorded in vitro in 4-, 7-, and 21-day-old rats. Suramin (100 μM) and A-317491 (10 μM) significantly depressed the sinus nerve chemosensory discharge rate (∼80%) in normoxia (Po2 ∼150 Torr) and hypoxia (Po2 ∼60 Torr), and this decrease was constant across ages. We conclude that, in newborn rats, P2X purinergic receptors are involved in the regulation of breathing under basal and hypoxic condition, and P2X3-containing receptors play a major role in carotid body function. However, these effects are not age dependent within the age range studied.
Caries Prevalence, Caries-Related Factors and Plaque pH in Adolescents with Long-Term Asthma
Authors: Stensson M. , Wendt L.-K. , Koch G. , Oldaeus G. , Lingström P. , Birkhed D.
Published: November 2010

The aim of the present case-control study was to investigate dental caries, various caries-related factors as well as gingival condition, in 12- to 16-year-olds with long-term asthma (n = 20) and a matched healthy control group (n = 20). Data on dietary and oral hygiene habits, numbers of mutans streptococci and lactobacilli in saliva were also obtained. The plaque pH drop after a sucrose rinse was measured up to 40 min at 2 approximal tooth sites. A lower salivary flow rate was found in the asthma group compared to the control group (p < 0.05). The mean (± SD) of DFS, including manifest and initial caries, was 4.9 ± 5.5 in the asthma and 1.4 ± 2.3 (p < 0.01) in the control group. Only 1 adolescent in the asthma group was caries free compared to 13 in the control group. Concerning pH in plaque, adolescents with asthma had a lower initial value (p < 0.01) and final pH (p < 0.05) than the control group. The Cariogram data showed that 55% of the subjects in the control group had ‘a high chance of avoiding caries’ compared to 10% in the asthma group (p < 0.01). The asthmatic adolescents had higher numbers of sites with gingival bleeding (p < 0.01). To conclude, adolescents with long-term asthma had a higher total DFS and caries risk (according to Cariogram), decreased salivary rate, more gingival bleeding and lower plaque pH than adolescents without asthma.
The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction
Authors: Caram Camila , de Souza Roberta Grazielle , de Sousa Júlio Carepa , Pereira Tatiana Araújo , Cerqueira Ana Maria do Amaral , van Der Bom Johanna , Rezende Suely Meireles
Published: November 2010

The development of alloantibodies that inhibit or neutralise the function of factor VIII is considered the most serious complication of the treatment of congenital haemophilia A. In order to describe their course without immune tolerance induction (ITI), we documented data on all performed inhibitor tests with dates as well as on clotting factor infusions of all consecutive patients who were treated in our centre between 1993 and 2006. Patients were tested every 7.1 months (95% confidence interval [CI], 6.6–7.8). A ‘sustained negative inhibitor status’ was defined as consistent non-positive inhibitor measurements for two years or longer. A total of 60/486 (12%) patients tested had a positive inhibitor titre in two or more occasions. Most of the patients (56%) with a maximum inhibitor titre of < 5 Bethesda unit (BU)/ml (named “low titre inhibitor”) developed a sustained negative inhibitor status. Among patients with high (5–9.9 BU/ml) and very high (≥ 10 BU/ ml) inhibitor titres, the proportions were 50% and 3%, respectively. Our findings suggest that ITI might not be needed for all patients with non-transient inhibitors, especially when their maximum inhibitor titre is below 10 BU/ml. Further studies in countries where ITI is not available are needed to examine predictors of the natural sustained negative inhibitor status.
Low insulin-like growth factor-1 levels are associated with anaemia in adult non-diabetic subjects
Authors: Succurro Elena , Arturi Franco , Caruso Vittoria , Rudi Stefania , Sciacqua Angela , Andreozzi Francesco , Hribal Marta , Perticone Francesco , Sesti Giorgio
Published: November 2010

Anaemia is a risk factor for cardiovascular morbidity and mortality. Among factors responsible for anaemia, insulin-like growth factor-1 (IGF-1) is a plausible candidate. We evaluated the association of IGF-1 with haemoglobin (Hb) concentration and anaemia in a cohort of 1,039 Caucasians subjects. Subjects with anaemia exhibited lower IGF-1 (p=0.006), and higher hsCRP levels (p=0.003). To estimate the independent contribution of variables to Hb concentration, a multivariable regression analysis was modeled including age, gender, body mass index (BMI), waist circumference, blood pressure, fasting glucose, fasting insulin, IGF-1, fibrinogen, hsCRP, mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), serum iron, estimated glomerular filtration rate (eGFR), and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). The variables significantly associated with Hb concentration were gender (p<0.0001), IGF-1 (p<0.0001), waist circumference (p=0.02), hsCRP (p<0.04), MCH (p<0.0001), MCV (p<0.0001), serum iron (p=0.001), IGF-1 (p=0.003), hsCRP (p=0.008), and waist circumference (p=0.01), accounting for 54.0% of its variation. Hb concentration was significant lower in subjects in the lowest IGF-1 quartile as compared with those in the third (p=0.02) and fourth (p=0.001). In a logistic regression model adjusted for age, gender, BMI, waist circumference, blood pressure, fasting glucose, fasting insulin, fibrinogen, hsCRP, MCH, MCV, serum iron, eGFR, and treatment with ACE inhibitors or ARBs, subjects in the first quartile of IGF-1 had a 2.49-fold higher risk of having anaemia as compared with those in the fourth (odds ratio 2.70, 95% confidence interval 1.02–7.16). Our data suggest that low IGF-1 may be an important contributor to mild anaemia.
High incidence of ankle arthropathy in mild and moderate haemophilia A
Authors: Ling Min , Heysen Jonathan Peter Hans , Duncan Elizabeth Mary , Rodgers Susan Elizabeth , Lloyd John Viner
Published: November 2010

A clinical study of patients with mild haemophilia A to document the frequency and severity of arthropathy has not been previously published. We studied ankle arthropathy in 34 patients with mild/moderate haemophilia A. The patients were assessed for the presence and severity of pain, and by the physical and radiological scoring systems for the evaluation of haemophilic arthropathy recommended by the World Federation of Haemophilia (WFH). Of the 34 patients, 16 (47%) had ankle pain, which was of moderate to severe degree in nine patients, and associated with limitation of physical activities in 13 patients. Of 33 patients examined by radiology 17 (52%) were positive for ankle arthropathy, and of these, 16 were also positive by the physical score. The presence and severity of ankle arthropathy was more common in patients with a one-stage factor VIII level of less than or equal to 11 IU/ dl. There was a significant relationship between the presence of ankle arthropathy and a history of bleeds into the ankle joint as a child. We conclude that arthropathy of the ankle in these patients is common, is often severe and disabling, and is due to episodes of bleeding into the ankle joint during childhood.
Study Design of the CLOSURE I Trial
Authors: Furlan Anthony J. , Reisman Mark , Massaro Joseph , Mauri Laura , Adams Harold , Albers Gregory W. , Felberg Robert , Herrmann Howard , Kar Saibal , Landzberg Michael , Raizner Albert , Wechsler Lawrence
Published: November 2010

Background and Purpose—

Some strokes of unknown etiology may be the result of a paradoxical embolism traversing through a nonfused foramen ovale (patent foramen ovale [PFO]). The utility of percutaneously placed devices for treatment of patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO is unknown. In addition, there are no clear data about the utility of medical interventions or other surgical procedures in this situation. Despite limited data, many patients are being treated with PFO closure devices. Thus, there is a strong need for clinical trials that test the potential efficacy of PFO occlusive devices in this situation. To address this gap in medical knowledge, we designed the CLOSURE I trial, a randomized, clinical trial comparing the use of a percutaneously placed PFO occlusive device and best medical therapy versus best medical therapy alone for prevention of recurrent ischemic neurologic symptoms among persons with TIA or ischemic stroke.

Study Design—

This prospective, multicenter, randomized, controlled trial has finished enrollment. Two-year follow-up for all 910 patients is required. The primary end point is the 2-year incidence of stroke or TIA, all-cause mortality for the first 30 days, and neurologic mortality from ≥31 days of follow-up, as adjudicated by a panel of physicians who are unaware of treatment allocation. This article describes the rationale and study design of CLOSURE I.

Conclusions—

This trial should provide information as to whether the STARFlex septal closure system is safe and more effective than best medical therapy alone in preventing recurrent stroke/TIA and mortality in patients with PFO and whether the STARFlex septal closure device can demonstrate superiority compared with best medical therapy alone.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00201461.
Predicting Risk of Perioperative Death and Stroke After Carotid Endarterectomy in Asymptomatic Patients
Authors: Calvillo-King Linda , Xuan Lei , Zhang Song , Tuhrim Stanley , Halm Ethan A.
Published: November 2010

Background and Purpose—

National guidelines on carotid endarterectomy (CEA) for asymptomatic patients state that the procedure should be performed with a ≤3% risk of perioperative death or stroke. We developed and validated a multivariate model of risk of death or stroke within 30 days of CEA for asymptomatic disease and a related clinical prediction rule.

Methods—

We analyzed asymptomatic cases in a population-based cohort of CEAs performed in Medicare beneficiaries in New York State. Medical records were abstracted for sociodemographics, neurologic history, disease severity, diagnostic imaging data, comorbidities, and deaths and strokes within 30 days of surgery. We used multivariate logistic regression to identify independent predictors of perioperative death or stroke. The CEA-8 clinical risk score was derived from the final model.

Results—

Among the 6553 patients, the mean age was 74 years, 55% were male, 62% had coronary artery disease, and 22% had a history of distant stroke or transient ischemic attack. The perioperative rate of death or stroke was 3.0%. Multivariable predictors of perioperative events were female sex (odds ratio [OR]=1.5; 95% CI, 1.1 to 1.9), nonwhite race (OR=1.8; 95% CI, 1.1 to 2.9), severe disability (OR=3.7; 95% CI, 1.8 to 7.7), congestive heart failure (OR=1.6; 95% CI, 1.1 to 2.4), coronary artery disease (OR=1.6; 95% CI, 1.2 to 2.2), valvular heart disease (OR=1.5; 95% CI, 1.1 to 2.3), a distant history of stroke or transient ischemic attack (OR=1.5; 95% CI, 1.1 to 2.0), and a nonoperated stenosis ≥50% (OR=1.8; 95% CI, 1.3 to 2.3). The CEA-8 risk score stratified patients with a predicted probability of death or stroke rate from 0.6% to 9.6%.

Conclusions—

Several sociodemographic, neurologic severity, and comorbidity factors predicted the risk of perioperative death or stroke in asymptomatic patients. The CEA-8 risk score can help clinicians calculate a predicted probability of complications for an individual patient to help inform the decision about revascularization.