bluuebunny/crossref_metadata_2025 huggingface dataset:
Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives
Authors: Sanders Natalie G. , Meyers David J. , Sullivan David J.
Published: November 2013

Quinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC
50
) of 100 to 200 nM against
Plasmodium falciparum
quinine-sensitive strain 3D7 (IC
50
, 56 nM). Only HEAQD demonstrated activity against quinine-tolerant
P. falciparum
strains Dd2 and INDO with IC
50
s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC
50
of 313 nM. In the lethal mouse malaria model
Plasmodium berghei
ANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC
50
≥ 90 μM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC
50
s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quinine
in vitro
and
in vivo
for
Plasmodium
inhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.
Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli
Authors: Opperman Timothy J. , Kwasny Steven M. , Kim Hong-Suk , Nguyen Son T. , Houseweart Chad , D'Souza Sanjay , Walker Graham C. , Peet Norton P. , Nikaido Hiroshi , Bowlin Terry L.
Published: November 2013

Members of the resistance-nodulation-division (RND) family of efflux pumps, such as AcrAB-TolC of
Escherichia coli
, play major roles in multidrug resistance (MDR) in Gram-negative bacteria. A strategy for combating MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the
Enterobacteriaceae
. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin versus
E. coli
AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC-deficient strains. MBX2319 (3.13 μM) in combination with 0.016 μg/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of
E. coli
AB1157 by 10,000-fold after 4 h of exposure, in comparison with 0.016 μg/ml CIP alone. In contrast, phenyl-arginine-β-naphthylamide (PAβN), a known EPI, did not increase the bactericidal activity of 0.016 μg/ml CIP at concentrations as high as 100 μM. MBX2319 increased intracellular accumulation of the fluorescent dye Hoechst 33342 in wild-type but not AcrAB-TolC-deficient strains and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against
Enterobacteriaceae
species and
Pseudomonas aeruginosa
. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens.
In Vitro
Spatial and Temporal Analysis of Mycoplasma pneumoniae Colonization of Human Airway Epithelium
Authors: Prince Oliver A. , Krunkosky Thomas M. , Krause Duncan C.
Published: November 2013

Mycoplasma pneumoniae
is an important cause of respiratory disease, especially in school-age children and young adults. We employed normal human bronchial epithelial (NHBE) cells in air-liquid interface culture to study the interaction of
M. pneumoniae
with differentiated airway epithelium. These airway cells, when grown in air-liquid interface culture, polarize, form tight junctions, produce mucus, and develop ciliary function. We examined both qualitatively and quantitatively the role of mycoplasma gliding motility in the colonization pattern of developing airway cells, comparing wild-type
M. pneumoniae
and mutants thereof with moderate to severe defects in gliding motility. Adherence assays with radiolabeled mycoplasmas demonstrated a dramatic reduction in binding for all strains with airway cell polarization, independent of acquisition of mucociliary function. Adherence levels dropped further once NHBE cells achieved terminal differentiation, with mucociliary activity strongly selecting for full gliding competence. Analysis over time by confocal microscopy demonstrated a distinct colonization pattern that appeared to originate primarily with ciliated cells, but lateral spread from the base of the cilia was slower than expected. The data support a model in which the mucociliary apparatus impairs colonization yet cilia provide a conduit for mycoplasma access to the host cell surface and suggest acquisition of a barrier function, perhaps associated with tethered mucin levels, with NHBE cell polarization.
Effects of strain on the band alignment and the optical gain of a CdTe/ZnTe quantum dot
Authors: Sangeetha R. , Peter A. John , Yoo Chang Kyoo
Published: November 2013

The band lineups at the strained layer interfaces, in ZnxCd1–xTe/ZnTe quantum dot nanostructure for various Zn alloy content, are computed using model solid theory with an example of CdTe/ZnTe interface. The effects of strain, due to hydrostatic and biaxial strain, and the internal electric fields, due to the spontaneous and piezoelectric polarization, are taken into consideration. The dielectric mismatch, through the effective potential, is introduced between the dielectric constants of the dot and the barrier materials. The interband emission energy as a function of dot radius is computed for various Zn alloy content. The optical gain spectra of heavy hole exciton for various Zn concentration are studied. Calculations are obtained for different confinement potentials with the inclusion strain effect. Our results show that (i) the potential taking into account the effects of PB potential due to the dielectric mismatch enhances the exciton binding energy and (ii) the geometry of quantum dot, the strain effects and the Zinc alloy content have great influences on the electrical and optical properties of the dot. Our results are in good agreement with the previous investigators.
A NEURAL OBSERVER WITH TIME-VARYING LEARNING RATE: ANALYSIS AND APPLICATIONS
Authors: GURUBEL K. J. , ALANIS A. Y. , SANCHEZ E. N. , CARLOS-HERNANDEZ S.
Published: November 2013

In this paper, a reduced order neural observer (RONO) with a time-varying learning rate is proposed. The proposed scheme is based on a discrete-time recurrent high order neural network (RHONN) trained with an extended Kalman filter (EKF)-based algorithm. A time-varying learning rate is designed in order to improve the learning of the neuronal network in presence of disturbances and parameter variations. This work includes the stability proof of the time-varying learning. The applicability of the developed observer is illustrated via simulations for a nonlinear anaerobic digestion process.
MANIFOLDS THAT ARE NOT LEAVES OF CODIMENSION ONE FOLIATIONS
Authors: SOUZA FÁBIO S. , SCHWEITZER PAUL A.
Published: November 2013

We present new open manifolds that are not homeomorphic to leaves of any C0 codimension one foliation of a compact manifold. Among them are simply connected manifolds of dimension d ≥ 5 that are non-periodic in homotopy, namely in their two-dimensional homotopy groups.
Simulation of two-phase fluid mixture flow in rectangular two-inlet cavity using lattice Boltzmann method
Authors: Qiu Ruofan , Wang Anlin , Gong Qiwei , Jiang Tao
Published: November 2013

In this paper, two-phase fluid mixture flow in rectangular two-inlet cavity is studied using lattice Boltzmann method (LBM). To simulate two-phase fluids with large viscosity difference, the pseudo-potential model is improved. The improved model is verified for surface tension through Laplace's law and shown much better performance in simulating fluids with large viscosity difference than pseudo-potential model. The multiple-relaxation-time (MRT) scheme is used to enhance numerical stability. Then the two-phase fluid mixture flow with same and different viscosity in two-inlet cavity is simulated by present lattice Boltzmann (LB) model, pseudo-potential LB model and volume-of-fluid (VOF) method, respectively. The comparison of these numerical results shows that LB model is more suitable for such kind of flow than VOF method, since it can reflect repulsive forces and transitional region of two-phase fluids in dynamic process. Moreover, it also shows that present LB model has better dynamic stability than pseudo-potential model. Furthermore, simulations of the two-phase fluid mixture flow with different fluid viscosities, inlet velocities, inlet heights and outlet positions using present LB model are presented, exhibiting their effect to contact area of fluids.
FOLDING EQUILATERAL PLANE GRAPHS
Authors: ABEL ZACHARY , DEMAINE ERIK D. , DEMAINE MARTIN L. , EISENSTAT SARAH , LYNCH JAYSON , SCHARDL TAO B. , SHAPIRO-ELLOWITZ ISAAC
Published: November 2013

We consider two types of folding applied to equilateral plane graph linkages. First, under continuous folding motions, we show how to reconfigure any linear equilateral tree (lying on a line) into a canonical configuration. By contrast, it is known that such reconfiguration is not always possible for linear (nonequilateral) trees and for (nonlinear) equilateral trees. Second, under instantaneous folding motions, we show that an equilateral plane graph has a noncrossing linear folded state if and only if it is bipartite. Furthermore, we show that the equilateral constraint is necessary for this result, by proving that it is strongly NP-complete to decide whether a (nonequilateral) plane graph has a linear folded state. Equivalently, we show strong NP-completeness of deciding whether an abstract metric polyhedral complex with one central vertex has a noncrossing flat folded state. By contrast, the analogous problem for a polyhedral manifold with one central vertex (single-vertex origami) is only weakly NP-complete.
Geotectonic evolution of Midland Scotland from Cambrian to Silurian: a review
Authors: Bluck B.J.
Published: November 2013

Synopsis

During its Lower Palaeozoic history, the Midland Valley of Scotland was subject to compression from the blocks on either side, confirming the views of Kennedy (1958). Cambrian–Llanvirn-aged rocks of the Hebridean craton formed part of a passive margin, which extended to the ESE and is now replaced by the metamorphic complexes of the Moine and Dalradian. Both blocks had undergone metamorphism, uplift and shedding of their covers elsewhere. The ophiolitic part of the Highland Border Complex, which may be a continuation of the structurally foreshortened and rotated Ballantrae Complex, was obducted at
c
.490 Ma and may have interacted with rocks of the Hebridean passive margin.

Ordovician rocks at Girvan are a small remnant of a one-time far larger forearc basin, which formed to the south of a major arc complex, originally situated in the Midland Valley and probably extending from somewhere in the North Sea to offshore Ireland and beyond. The Highland Border Complex includes rocks coeval with the Midland Valley arc at
c
.470 Ma that formed a back-arc basin.

The Southern Uplands have converged on the Midland Valley, with the forearc sequence apparently missing in Scotland. Part of that convergence history is recorded in the Silurian conglomerates of the southern Midland Valley. Silurian sequences in this area contain conglomerates and breccias, derived from the south that record the presence of an igneous and possibly also a metamorphic complex in the region now occupied by the trench sequence of the Southern Uplands. It is suggested that the trench was later thrust over this source block and that the Southern Upland Fault forms part of that thrust sequence.

The metamorphic complexes to the north, replacing the Hebridean passive margin, did not interact with the Midland Valley until Lower Devonian times. It follows that there was no mountain-building orogeny in Scotland, other than an arc, a sliver of trench, and numerous examples of crustal contraction by strike-slip and/or thrusting.
Application of the Local Fractional Series Expansion Method and the Variational Iteration Method to the Helmholtz Equation Involving Local Fractional Derivative Operators
Authors: Yang Ai-Min , Chen Zeng-Shun , Srivastava H. M. , Yang Xiao-Jun
Published: November 2013

We investigate solutions of the Helmholtz equation involving local fractional derivative operators. We make use of the series expansion method and the variational iteration method, which are based upon the local fractional derivative operators. The nondifferentiable solution of the problem is obtained by using these methods.
Modeling and Analysis of Online Delay of Nonperiodic CAN Message
Authors: Wang Dafang , Yang Bowen , Jin Yi , Qi Ji , Li Nannan
Published: November 2013

In order to analyze the online communication delay of nonperiodic CAN message, the mathematical model of average on-line delay is established based on M/G/1 queuing theory and an experimental platform is designed to analyze the delay of CAN communication, with which the on-line delays of messages with a different ID are tested at different load ratios. The results show that the model is very close to the actual situation indicating the high accuracy of the model. In the results, for the same message, the average and maximum online delays both increase with the raise of load ratio. At the same load ratio, the maximum on-line delay increases with the decrease of the message priority, and the average on-line delay remains almost unchanged.
A Hybrid Multiobjective Differential Evolution Algorithm and Its Application to the Optimization of Grinding and Classification
Authors: Wang Yalin , Chen Xiaofang , Gui Weihua , Yang Chunhua , Caccetta Lou , Xu Honglei
Published: November 2013

The grinding-classification is the prerequisite process for full recovery of the nonrenewable minerals with both production quality and quantity objectives concerned. Its natural formulation is a constrained multiobjective optimization problem of complex expression since the process is composed of one grinding machine and two classification machines. In this paper, a hybrid differential evolution (DE) algorithm with multi-population is proposed. Some infeasible solutions with better performance are allowed to be saved, and they participate randomly in the evolution. In order to exploit the meaningful infeasible solutions, a functionally partitioned multi-population mechanism is designed to find an optimal solution from all possible directions. Meanwhile, a simplex method for local search is inserted into the evolution process to enhance the searching strategy in the optimization process. Simulation results from the test of some benchmark problems indicate that the proposed algorithm tends to converge quickly and effectively to the Pareto frontier with better distribution. Finally, the proposed algorithm is applied to solve a multiobjective optimization model of a grinding and classification process. Based on the technique for order performance by similarity to ideal solution (TOPSIS), the satisfactory solution is obtained by using a decision-making method for multiple attributes.
E. coliEndotoxin Modulates the Expression of Sirtuin Proteins in PBMC in Humans
Authors: Storka Angela , Führlinger Gerhard , Seper Martin , Wang Lisa , Jew Michael , Leisser Asha , Wolzt Michael
Published: November 2013

Background. Sirtuin (SIRT) proteins are class I histone deacetylases displaying gene regulatory functions in inflammatory, cancer, and metabolic diseases. These SIRT actions involve the nuclear factorκB and its inhibitor IκB pathway. However, the regulation of SIRTin vivois still unclear.Material and Methods. In a human endotoxemia model, 20 healthy male subjects received an intravenous bolus of 2 ng/kg body weightEscherichia coliendotoxin (LPS). SIRT expression was investigated in peripheral blood mononuclear cells (PBMC) with qPCR and Western blot before and 3 hours, 6 hours, and 24 hours after LPS challenge. Additionally, SIRT regulation was studiedin vitroin cultivated PBMC after incubation with 20 ng/mL LPS.Results. A downregulation by >40% of SIRT1 mRNA was detectable 3 hours after LPS and of SIRT3 mRNA 6 hours after LPS. SIRT3, IκBα, and IκB-βprotein expressions were decreased 3 and 6 hours after LPS. SIRT2 mRNA or protein expression did not change following LPS. These findings were consistentin vitroand associated with augmented phosphorylation of IκB-β.Discussion. In thisE. coliendotoxemia model, SIRT1 and SIRT3 mRNA expressions in PBMC in humans were reduced after LPS challenge. This suggests that SIRT may represent an inflammatory target proteinin vivo.
Retroperitoneal Lipoma Presenting with Nutcracker-Like Phenomenon
Authors: Saito Seiichi
Published: November 2013

Retroperitoneal lipoma presenting with a nutcracker-like phenomenon is extremely rare. I experienced a case of a 65-year-old man presenting with left flank pain and macrohematuria intermittently for 3 years. Computed tomography revealed a lipoma at the left pedicle of the kidney, 30 mm in diameter, causing a curving of the left renal artery and dilatation of the left renal vein. This patient was treated successfully by retroperitoneoscopic resection of the lipoma. There have been no symptoms for 10 years after the operation.
Electronic Nose Based on Nanomaterials: Issues, Challenges, and Prospects
Authors: Ramgir Niranjan S.
Published: November 2013

The ability to precisely control the morphology and dimension coupled with the tunable surface reactivity has led to the widespread investigation of nanomaterials for various device applications. The associated high surface area to volume ratio implies that large numbers of atom are residing on the surface and are available for interaction. Accordingly, nanomaterials have demonstrated the potential to realize sensors with ultrahigh sensitivities and fast response kinetics. The smaller size further provides the possibility of miniaturization and integration of large number of devices. All these properties makes them an attractive candidate for the fabrication of electronic nose or e-nose. E-nose is an intelligent chemical-array sensor system that mimics the mammalian olfactory system. The present paper critically reviews the recent development in the field of nanomaterials based e-nose devices. In particular, this paper is focused on the description of nanomaterials for e-nose application, specifically on the promising approaches that are going to contribute towards the further development of this field. Various issues related to successful utilization of different nanomaterials for commercial application are discussed, taking help from the literature. The review concludes by briefing the important steps taken towards the commercialization and highlighting the loopholes that are still to be addressed.
The High-Affinity CXCR4 Antagonist BKT140 Is Safe and Induces a Robust Mobilization of Human CD34+ Cells in Patients with Multiple Myeloma
Authors: Peled Amnon , Abraham Michal , Avivi Irit , Rowe Jacob M. , Beider Katia , Wald Hanna , Tiomkin Lena , Ribakovsky Lena , Riback Yossi , Ramati Yaron , Aviel Sigal , Galun Eithan , Shaw Howard Laurence , Eizenberg Orly , Hardan Izhar , Shimoni Avichai , Nagler Arnon
Published: November 2013

Purpose: CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.

Experimental Design: Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m2 cyclophosphamide (day 0), followed by granulocyte colony—stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.

Results: BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34+ cells (20.6 ± 6.9 × 106/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 106 CD34+ cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).

Conclusions: When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34+ cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment. Clin Cancer Res; 20(2); 469–79. ©2013 AACR.
Tumoral Immune Suppression by Macrophages Expressing Fibroblast Activation Protein-α and Heme Oxygenase-1
Authors: Arnold James N. , Magiera Lukasz , Kraman Matthew , Fearon Douglas T.
Published: November 2013

The depletion of tumor stromal cells that are marked by their expression of the membrane protein fibroblast activation protein-α (FAP) overcomes immune suppression and allows an anticancer cell immune response to control tumor growth. In subcutaneous tumors established with immunogenic Lewis lung carcinoma cells expressing ovalbumin (LL2/OVA), the FAP+ population is comprised of CD45+ and CD45− cells. In the present study, we further characterize the tumoral FAP+/CD45+ population as a minor subpopulation of F4/80hi/CCR2+/CD206+ M2 macrophages. Using bone marrow chimeric mice in which the primate diphtheria toxin receptor is restricted either to the FAP+/CD45+ or to the FAP+/CD45− subset, we demonstrate by conditionally depleting each subset that both independently contribute to the immune-suppressive tumor microenvironment. A basis for the function of the FAP+/CD45+ subset is shown to be the immune inhibitory enzyme, heme oxygenase-1 (HO-1). The FAP+/CD45+ cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Because this observation of immune suppression by HO-1 expressed by the FAP+/CD45+ stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy. Cancer Immunol Res; 2(2); 121–6. ©2013 AACR.
Neuron-Specific (Pro)renin Receptor Knockout Prevents the Development of Salt-Sensitive Hypertension
Authors: Li Wencheng , Peng Hua , Mehaffey Eamonn P. , Kimball Christie D. , Grobe Justin L. , van Gool Jeanette M.G. , Sullivan Michelle N. , Earley Scott , Danser A.H. Jan , Ichihara Atsuhiro , Feng Yumei
Published: November 2013

The (pro)renin receptor (PRR), which binds both renin and prorenin, is a newly discovered component of the renin–angiotensin system that is highly expressed in the central nervous system. The significance of brain PRRs in mediating local angiotensin II formation and regulating blood pressure remains unclear. The current study was performed to test the hypothesis that PRR-mediated, nonproteolytic activation of prorenin is the main source of angiotensin II in the brain. Thus, PRR knockout in the brain is expected to prevent angiotensin II formation and development of deoxycorticosterone acetate-salt–induced hypertension. A neuron-specific PRR (ATP6AP2) knockout mouse model was generated using the Cre-LoxP system. Physiological parameters were recorded by telemetry. PRR expression, detected by immunostaining and reverse transcription–polymerase chain reaction, was significantly decreased in the brains of knockout mice compared with wild-type mice. Intracerebroventricular infusion of mouse prorenin increased blood pressure and angiotensin II formation in wild-type mice. This hypertensive response was abolished in PRR-knockout mice in association with a reduction in angiotensin II levels. Deoxycorticosterone acetate-salt increased PRR expression and angiotensin II formation in the brains of wild-type mice, an effect that was attenuated in PRR-knockout mice. PRR knockout in neurons prevented the development of deoxycorticosterone acetate-salt–induced hypertension as well as activation of cardiac and vasomotor sympathetic tone. In conclusion, nonproteolytic activation of prorenin through binding to the PRR mediates angiotensin II formation in the brain. Neuron-specific PRR knockout prevents the development of deoxycorticosterone acetate-salt–induced hypertension, possibly through diminished angiotensin II formation.
Myocardial Damage Detected by Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Is Associated With Subsequent Hospitalization for Heart Failure
Authors: Wong Timothy C. , Piehler Kayla M. , Zareba Karolina M. , Lin Kathie , Phrampus Ashley , Patel Agam , Moon James C. , Ugander Martin , Valeti Uma , Holtz Jonathan E. , Fu Bo , Chang Chung‐Chou H. , Mathier Michael , Kellman Peter , Butler Javed , Gheorghiade Mihai , Schelbert Erik B.
Published: November 2013

Background

Hospitalization for heart failure (
HHF
) is among the most important problems confronting medicine. Late gadolinium enhancement (
LGE
) cardiovascular magnetic resonance (
CMR
) robustly identifies intrinsic myocardial damage.
LGE
may indicate inherent vulnerability to
HHF
, regardless of etiology, across the spectrum of heart failure stage or left ventricular ejection fraction (
LVEF
).

Methods and Results

We enrolled 1068 consecutive patients referred for
CMR
where 448 (42%) exhibited
LGE
. After a median of 1.4 years (Q1 to Q3: 0.9 to 2.0 years), 57
HHF
events occurred, 15 deaths followed
HHF
, and 43 deaths occurred without antecedent
HHF
(58 total deaths). Using multivariable
C
ox regression adjusting for
LVEF
, heart failure stage, and other covariates,
LGE
was associated with first
HHF
after
CMR
(
HR
: 2.70, 95%
CI
: 1.32 to 5.50), death (
HR
: 2.13, 95%
CI
: 1.08 to 4.21), or either death or
HHF
(
HR
: 2.52, 95%
CI
: 1.49 to 4.25). Quantifying
LGE
extent yielded similar results; more
LGE
equated higher risks.
LGE
improved model discrimination (
IDI
: 0.016, 95%
CI
: 0.005 to 0.028,
P
=0.002) and reclassification of individuals at risk (continuous
NRI
: 0.40, 95%
CI
: 0.05 to 0.70,
P
=0.024). Adjustment for competing risks of death that shares common risk factors with
HHF
strengthened the
LGE
and
HHF
association (
HR
: 4.85, 95%
CI
: 1.40 to 16.9).

Conclusions

The presence and extent of
LGE
is associated with vulnerability for
HHF,
including higher risks of
HHF
across the spectrum of heart failure stage and
LVEF
. Even when
LVEF
is severely decreased, those without
LGE
appear to fare reasonably well.
LGE
may enhance risk stratification for
HHF
and may enhance both clinical and research efforts to reduce
HHF
through targeted treatment.
The Doctrines of Public Policy and Competence in Investor–State Arbitration
Authors: Ayad Mary B.
Published: November 2013

Abstract

International commercial arbitration (ICA) and international investment arbitration (IIA), as they are currently practiced in the Middle East and North Africa (MENA) inter alia, cannot be seen in isolation. Long-standing historical forces have brought about both the development of jurisprudence as well as its current problems. In arbitrations in which one party is a MENA State, from the early oil concessions throughout the present, ICA and IIA law and practise have demonstrated that the central problem therein has to do with a conflict of laws. What is proposed herein is that common legal principles found in civil, common and Islamic law, which form part or all of the legal systems in the MENA, can be distilled to create a new ICA law code for adoption in the MENA; a code which addresses many of the doctrinal issues that arise in ICA and IIA proceedings. To this end, this article presents the results of this highly practical research which represents a synthesis of theory and practise.
Developing the Legal Environment for Business in the Kingdom of Saudi Arabia: Comments and Suggestions
Authors: Alshubaiki Torki A.
Published: November 2013

Abstract

Closing the door of ijtihād or independent reasoning in the 10th century resulted in a legal system that was often at odds with the modern world, especially in the area of contracts. Although it is considered to be a big breakthrough at the present time that some of the religious figures or ulama in Saudi Arabia have finally expressed their interest in the codification of laws, the issue has to be dealt with from a different, not only religious, perspective. The importance of comparative law must be expressed when dealing with all commercial matters. Promoting and encouraging intellectual curiosity in different legal areas through academic institutions and research centres will drive the scholars to study the commercial law subjects from a number of different perspectives. In that process, they will develop a better understanding of their own system and know the way of developing it.
A Cross-Laboratory Investigation of Timing Endophenotypes in Mouse Behavior
Authors: Maggi Silvia , Garbugino Luciana , Heise Ines , Nieus Thierry , Balcı Fuat , Wells Sara , Tocchini-Valentini Glauco P. , Mandillo Silvia , Nolan Patrick M. , Tucci Valter
Published: November 2013

Phenotyping behavioral and cognitive processes is a critical practice in mouse research and reliable phenotypic assessment is an essential component of building well-defined links between genes and behavioral/cognitive functions.

The success of behavioral screens in neurobehavioral mouse genetics depends on the identification of reliable, reproducible, and high-throughput behavioral/cognitive measures from individual animals irrespective of the differences in opinions regarding how to tackle phenotyping in different behavioral domains. Furthermore, reliable behavioral assays must be resistant to inevitable environmental differences across laboratories since protocols can be replicated but not all the environmental conditions.

Here we present a cross-laboratory study of interval timing behaviors in mice. Two classically used mouse inbred substrains, C57BL/6J and C57BL/6N, were studied over several days in home-cages containing automated testing apparatus. Remarkably, all timing measures in mouse performance showed a robust reproducibility across centers and even small differences between the two substrains were comparable across laboratories. Moreover, we have observed a consistent increase in error rate during the light phase of the light–dark cycle, which suggests that mouse performance during this phase is compromised by a possible sleep inertia-like effect. Overall, our study demonstrates that analysis of mouse timing behavior can lead to robust and reliable endophenotypes in mouse behavioral genetic studies.
Treatment of Aortoiliac Aneurysms With the Iliac Bifurcated Device for Preservation of Internal Iliac Artery Flow
Authors: Chowdhury Mohammed M. , Schiro Andrew , Farquharson Finn , Smyth J. V. , Serracino-Inglott Ferdinand , Murray David
Published: November 2013

Introduction:

The iliac bifurcated device (IBD) is an innovative endovascular device for aortoiliac aneurysm repair. The objective of this study is to provide further evidence on the efficacy and safety of the device.

Study Design:

Case series study with retrospective analysis of prospectively collected nonrandomized data.

Methods:

Between 2007 and 2010, all consecutive IBD placements were analyzed. The main outcomes included (1) technical failure; (2) morbidity and mortality; and (3) late outcomes. Prospective follow-up was performed by interval computed tomography scanning.

Results:

In all, 27 consecutive patients had elective placement of 28 IBDs. Mean operating time was 251.1 ± 65.4 minutes, mean fluoroscopy time was 63.9 ± 27.2 minutes, and mean contrast volume used was 186.2 ± 106.7 mL. Periprocedural type I endoleak occurred in 2 patients. No aneurysm-related adverse events were recorded.

Conclusion:

We demonstrate that IBDs can be used in patients with aortoiliac aneurysms and are associated with satisfactory medium-term results as expressed by high patency and low reintervention rates.
Functional equations and inequalities in matrix paranormed spaces
Authors: Park Choonkil , Lee Jung Rye , Shin Dong Yun
Published: November 2013

In this paper, we prove the Hyers-Ulam stability of the Cauchy additive functional inequality, the Cauchy additive functional equation and the quadratic functional equation in matrix paranormed spaces.

MSC:47L25, 39B82, 39B72, 46L07, 39B52, 39B62.
Metachronous, colitis-associated rectal cancer that developed after sporadic adenocarcinoma in an adenoma in a patient with longstanding Crohn’s disease: a case report
Authors: Takeyama Hiroshi , Mizushima Tsunekazu , Nakajima Kiyokazu , Uemura Mamoru , Haraguchi Naotsugu , Nishimura Junichi , Hata Taishi , Takemasa Ichiro , Yamamoto Hirofumi , Doki Yuichiro , Mori Masaki
Published: November 2013

Background

Colorectal cancer associated with Crohn’s disease (CD) is increasing in proportion to the number of patients with CD in Japan. There are two subtypes of colorectal cancer with CD: sporadic cancer and colitis-associated cancer. Early diagnosis of colitis-associated cancer is sometimes difficult; when colorectal cancer is found in patients with CD, both colitis-associated cancer and sporadic cancer should be kept in mind. Here, we describe a case of metachronous, colitis-associated rectal cancer that developed after the complete resection of an adenoma that became a sporadic adenocarcinoma in a patient with longstanding CD. To the best of our knowledge, this is the first report of colitis-associated cancer in a patient with CD after removal of a sporadic cancer.

Case presentation

We describe a 51-year old man with CD who had difficulty in defecation. A rectal polyp was detected and a transanal resection of the polyp was performed. A histopathological examination showed an adenoma with sporadic adenocarcinoma. After three years, a follow-up colonoscopy revealed a reddish, elevated lesion in the patient’s rectum. A colonoscopic biopsy showed a signet ring cell carcinoma. We performed an abdominoperineal resection of the rectum and a bilateral pelvic lymph node dissection. A histopathological examination revealed a mucinous adenocarcinoma with signet ring cell carcinoma and lymph node metastasis. The patient received adjuvant chemotherapy with oral uracil 224 mg combined with tegafur 100 mg plus leucovorin. No signs of recurrence were noted at a follow-up 18 months after the third surgery and 60 months after the second surgery.
Cardiogenic shock accompanied by dynamic left ventricular outflow tract obstruction and myocardial bridging after transient complete atrioventricular block mimicking ST-elevation myocardial infarction: a case report
Authors: Kang Seonghui , An Sanghee , Yu Hyung Min , Kim Jiwan , Kim Sung Hea , Kim Hyun-Joong , Chung Sang Man
Published: November 2013

Background

Dynamic left ventricular outflow tract obstruction with or without mitral regurgitation is typically observed in hypertrophic cardiomyopathy, but is also occasionally seen without left ventricular hypertrophy. In this report, we present a case of cardiogenic shock that mimics ST-elevation myocardial infarction, due to dynamic left ventricular outflow tract obstruction with transient mitral regurgitation and myocardial bridging after transient complete atrioventricular block.

Case presentation

A 65-year-old man with hypertension presented himself at the emergency department with syncope after chest pain. His initial electrocardiography showed inferior ST elevation with profound precordial ST depression and transient complete atrioventricular block. Due to sustained hypotension, an intra-aortic balloon pump was applied. His coronary angiography revealed almost normal right coronary artery and left circumflex artery and only a severe myocardial bridge in the mid-segment of his left anterior descending artery. Instead, severe mitral regurgitation was found without regional wall motion abnormality both in the left ventriculography and the portable echocardiography. However the severe mitral regurgitation completely disappeared in follow up echocardiography the day after. The pressure gradient across the left ventricular outflow tract was measured at 8.95 mmHg during the resting state, and was increased to 38.95 mmHg during the Valsalva state.

Conclusions

The patient presented with a case of cardiogenic shock that mimicked ST-elevation myocardial infarction due to dynamic left ventricular outflow tract obstruction combined with myocardial bridging in the mid-left anterior descending artery.
Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice
Authors: Impellizzeri Daniela , Esposito Emanuela , Di Paola Rosanna , Ahmad Akbar , Campolo Michela , Peli Angelo , Morittu Valeria Maria , Britti Domenico , Cuzzocrea Salvatore
Published: November 2013

Introduction

N-palmitoylethanolamine (PEA) is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs). Recently, several studies demonstrated that PEA is an important analgesic, antiinflammatory, and neuroprotective mediator. The aim of this study was to investigate the effect of co-ultramicronized PEA + luteolin formulation on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA).

Methods

CIA was induced by an intradermally injection of 100 μl of the emulsion (containing 100 μg of bovine type II collagen (CII)) and complete Freund adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Mice subjected to CIA were administered PEA (10 mg/kg 10% ethanol, intraperitoneally (i.p.)) or co-ultramicronized PEA + luteolin (1 mg/kg, i.p.) every 24 hours, starting from day 25 to 35.

Results

Mice developed erosive hind-paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as periarticular erythema and edema in the hindpaws. The incidence of CIA was 100% by day 28 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period with a resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint. Treatment with PEA or PEA + luteolin ameliorated the clinical signs at days 26 to 35 and improved histologic status in the joint and paw. The degree of oxidative and nitrosative damage was significantly reduced in PEA + luteolin-treated mice, as indicated by nitrotyrosine and malondialdehyde (MDA) levels. Plasma levels of the proinflammatory cytokines and chemokines were significantly reduced by PEA + luteolin treatment.

Conclusions

We demonstrated that PEA co-ultramicronized with luteolin exerts an antiinflammatory effect during chronic inflammation and ameliorates CIA.
A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors
Authors: Hudis Clifford , Swanton Charles , Janjigian Yelena Y , Lee Ray , Sutherland Stephanie , Lehman Robert , Chandarlapaty Sarat , Hamilton Nicola , Gajria Devika , Knowles James , Shah Jigna , Shannon Keith , Tetteh Ernestina , Sullivan Daniel M , Moreno Carolina , Yan Li , Han Hyo Sook
Published: November 2013

Introduction

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.

Methods

Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.

Results

A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.

Conclusions

Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.

Trial registration

ClinicalTrials.gov; identifier: NCT00963547.
Pro–Surfactant Protein B As a Biomarker for Lung Cancer Prediction
Authors: Sin Don D. , Tammemagi C. Martin , Lam Stephen , Barnett Matt J. , Duan Xiaobo , Tam Anthony , Auman Heidi , Feng Ziding , Goodman Gary E. , Hanash Samir , Taguchi Ayumu
Published: November 2013

Purpose

Preliminary studies have identified pro–surfactant protein B (pro-SFTPB) to be a promising blood biomarker for non–small-cell lung cancer. We conducted a study to determine the independent predictive potential of pro-SFTPB in identifying individuals who are subsequently diagnosed with lung cancer.

Patients and Methods

Pro-SFTPB levels were measured in 2,485 individuals, who enrolled onto the Pan-Canadian Early Detection of Lung Cancer Study by using plasma sample collected at the baseline visit. Multivariable logistic regression models were used to evaluate the predictive ability of pro-SFTPB in addition to known lung cancer risk factors. Calibration and discrimination were evaluated, the latter by an area under the receiver operating characteristic curve (AUC). External validation was performed with samples collected in the Carotene and Retinol Efficacy Trial (CARET) participants using a case-control study design.

Results

Adjusted for age, sex, body mass index, personal history of cancer, family history of lung cancer, forced expiratory volume in one second percent predicted, average number of cigarettes smoked per day, and smoking duration, pro-SFTPB (log transformed) had an odds ratio of 2.220 (95% CI, 1.727 to 2.853; P < .001). The AUCs of the full model with and without pro-SFTPB were 0.741 (95% CI, 0.696 to 0.783) and 0.669 (95% CI, 0.620 to 0.717; difference in AUC P < .001). In the CARET Study, the use of pro-SFPTB yielded an AUC of 0.683 (95% CI, 0.604 to 0.761).

Conclusion

Pro-SFTPB in plasma is an independent predictor of lung cancer and may be a valuable addition to existing lung cancer risk prediction models.
Studies of translational misreading in vivo show that the ribosome very efficiently discriminates against most potential errors
Authors: Manickam Nandini , Nag Nabanita , Abbasi Aleeza , Patel Kishan , Farabaugh Philip J.
Published: November 2013

Protein synthesis must rapidly and repeatedly discriminate between a single correct and many incorrect aminoacyl-tRNAs. We have attempted to measure the frequencies of all possible missense errors by tRNA, tRNA and tRNA. The most frequent errors involve three types of mismatched nucleotide pairs, U•U, U•C, or U•G, all of which can form a noncanonical base pair with geometry similar to that of the canonical U•A or C•G Watson–Crick pairs. Our system is sensitive enough to measure errors at other potential mismatches that occur at frequencies as low as 1 in 500,000 codons. The ribosome appears to discriminate this efficiently against any pair with non-Watson–Crick geometry. This extreme accuracy may be necessary to allow discrimination against the errors involving near Watson–Crick pairing.
Venezuelan Democracy in the 20th Century
Authors: Da Silva P. José Luis
Published: November 2013

Twentieth‑century Venezuela has characteristics that make it different in terms of the ways of conducting politics in the traditional way. Political parties of the twentieth century inaugurated a new political period. One reason for this may be found in the long dictatorship of General Gómez which lasted for more than three decades and which obliterated all vestiges of nineteenth century politics to the point that students will be called to establish innovative proposals. The mode of policy‑making shows a difference in style between the military and non‑military along with irreconcilable difference in the perception of democracy which they showed. One mentoring system will come increasingly into a conflict with another, in which there is an attempt to make the citizens bear republican responsibilities in order to feed a state that at times runs the risk of collapse due to the unmet requirements of the people, together with other requirements of the time.
Community Archaeology in Los Roques Archipielago National Park, Venezuela
Authors: Antczak Andrzej , Antczak Maria Magdalena , Gonzalez Hurtado Gustavo , Antczak Konrad A.
Published: November 2013

Convinced that archaeology as a past‑ oriented discipline should exert a transformative impact on the present, we discuss a series of initiatives that aim at interweaving the past of the Los Roques Archipelago, located 135 km off the central coast of Venezuela, into its present‑ day community life. Pioneering archaeological research carried out on these islands since 1982 revealed an unexpectedly rich volume of diversified artifacts and contextual information on the Amerindian seamen who seasonally exploited the local natural resources between A.D. 1200 and 1500. We are confident that despite the historical discontinuity between the pre‑ Hispanic seamen and the current population of the archipelago, the vibrant and colorful archaeological past will reach the present‑ day inhabitants, enriching their socio‑ cultural identity and influencing their way of life that currently oscillates entrapped between fishing and tourism‑ oriented activities. We discuss the aims and methodology of community archeology activities that include talks, exhibits, publications, documentary films and – above all – archaeological workshops that bring together the archaeologists and Los Roques schoolchildren in experiential archaeological events.