bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Azithromycin Pharmacokinetics following Single Oral Doses of Extended-Release and Immediate-Release Formulations in Children with Acute Otitis Media
Authors: Liu Ping , Fang Annie F. , LaBadie Robert R. , Crownover Penelope H. , Arguedas Adriano G.
Published: August 2011

An azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (
n
= 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC
0-72
) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC
0-72
and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC
0-72
was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ≥80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin.
Environmental Microbiota Represents a Natural Reservoir for Dissemination of Clinically Relevant Metallo-β-Lactamases
Authors: Scotta Claudia , Juan Carlos , Cabot Gabriel , Oliver Antonio , Lalucat Jorge , Bennasar Antonio , Albertí Sebastián
Published: August 2011

A total of 10 metallo-β-lactamase-producing isolates of six different species, including
Brevundimonas diminuta
(
n
= 3),
Rhizobium radiobacter
(
n
= 2),
Pseudomonas monteilii
(
n
= 1),
Pseudomonas aeruginosa
(
n
= 2),
Ochrobactrum anthropi
(
n
= 1), and
Enterobacter ludwigii
(
n
= 1), were detected in the sewage water of a hospital. The presence of
bla
VIM-13
associated with a Tn
1721
-class 1 integron structure was detected in all but one of the isolates (
E. ludwigii
, which produced VIM-2), and in two of them (
R. radiobacter
), this structure was located on a plasmid, suggesting that environmental bacteria represent a reservoir for the dissemination of clinically relevant metallo-β-lactamase genes.
Identification of Inflammatory Biomarkers for Pediatric Malarial Anemia Severity Using Novel Statistical Methods
Authors: Ong'echa John M. , Davenport Gregory C. , Vulule John M. , Hittner James B. , Perkins Douglas J.
Published: August 2011

Areas where
Plasmodium falciparum
transmission is holoendemic are characterized by high rates of pediatric severe malarial anemia (SMA) and associated mortality. Although the etiology of SMA is complex and multifactorial, perturbations in inflammatory mediator production play an important role in the pathogenic process. As such, the current study focused on identification of inflammatory biomarkers in children with malarial anemia. Febrile children (3 to 30 months of age) presenting at Siaya District Hospital in western Kenya underwent a complete clinical and hematological evaluation. Children with falciparum malaria and no additional identifiable anemia-promoting coinfections were stratified into three groups: uncomplicated malaria (hemoglobin [Hb] levels of ≥11.0 g/dl;
n
= 31), non-SMA (Hb levels of 6.0 to 10.9 g/dl;
n
= 37), and SMA (Hb levels of <6.0 g/dl;
n
= 80). A Luminex hu25-plex array was used to determine potential biomarkers (i.e., interleukin 1β [IL-1β], IL-1 receptor antagonist [IL-1Ra], IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, tumor necrosis factor alpha [TNF-α], alpha interferon [IFN-α], IFN-γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β, IFN-inducible protein of 10 kDa [IP-10], monokine induced by IFN-γ [MIG], eotaxin, RANTES, and monocyte chemoattractant protein 1 [MCP-1]) in samples obtained prior to any treatment interventions. To determine the strongest biomarkers of anemia, a parsimonious set of predictor variables for Hb was generated by least-angle regression (LAR) analysis, controlling for the confounding effects of age, gender, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and sickle cell trait, followed by multiple linear regression analyses. IL-12p70 and IFN-γ emerged as positive predictors of Hb, while IL-2R, IL-13, and eotaxin were negatively associated with Hb. The results presented here demonstrate that the IL-12p70/IFN-γ pathway represents a set of biomarkers that predicts elevated Hb levels in children with falciparum malaria, while activation of the IL-13/eotaxin pathway favors more profound anemia.
Resistance to Yersinia pestis Infection Decreases with Age in B10.T(6R) Mice
Authors: Lambert Nathaniel D. , Langfitt Deanna M. , Nilles Matthew L. , Bradley David S.
Published: August 2011

We demonstrate that 2-month-old female B10.T(6R) mice are highly resistant to systemic infection with the KIM5 strain ofYersinia pestisand that B10.T(6R) mice become susceptible toY. pestisinfection by the age of 5 months. In this study, young (2-month-old) and middle-aged (5- to 12-month-old) B10.T(6R) mice were infected with equal CFU counts ofY. pestis. The 50% lethal dose (LD50) for young B10.T(6R) mice was ∼1.4 × 104CFU, while middle-aged B10.T(6R) mice exhibited an LD50of ∼60 CFU. Elevated bacterial burdens were found in the spleens of middle-aged mice at 24 and 60 h and in the livers at 60 h postinfection. Immune cell infiltration was greater in the livers of resistant young mice than in those of middle-aged mice and mice of the susceptible C57BL/6N strain. Unlike susceptible mice, young B10.T(6R) mice did not develop necrotic lesions throughout the liver. Instead, livers from young B10.T(6R) mice contained granuloma-like structures. Immunohistochemical staining of liver sections from these mice at 60 h postinfection revealed that the majority of immune cells present in these structures were neutrophils. These findings suggest that resistance to plague in B10.T(6R) mice correlates with early formation of neutrophilic lesions in the liver.
SadA, a Trimeric Autotransporter from Salmonella enterica Serovar Typhimurium, Can Promote Biofilm Formation and Provides Limited Protection against Infection
Authors: Raghunathan Dhaarini , Wells Timothy J. , Morris Faye C. , Shaw Robert K. , Bobat Saeeda , Peters Sarah E. , Paterson Gavin K. , Jensen Karina Tveen , Leyton Denisse L. , Blair Jessica M. A. , Browning Douglas F. , Pravin John , Flores-Langarica Adriana , Hitchcock Jessica R. , Moraes Claudia T. P. , Piazza Roxane M. F. , Maskell Duncan J. , Webber Mark A. , May Robin C. , MacLennan Calman A. , Piddock Laura J. , Cunningham Adam F. , Henderson Ian R.
Published: August 2011

Salmonella enterica
is a major cause of morbidity worldwide and mortality in children and immunocompromised individuals in sub-Saharan Africa. Outer membrane proteins of
Salmonella
are of significance because they are at the interface between the pathogen and the host, they can contribute to adherence, colonization, and virulence, and they are frequently targets of antibody-mediated immunity. In this study, the properties of SadA, a purported trimeric autotransporter adhesin of
Salmonella enterica
serovar Typhimurium, were examined. We demonstrated that SadA is exposed on the
Salmonella
cell surface
in vitro
and
in vivo
during infection of mice. Expression of SadA resulted in cell aggregation, biofilm formation, and increased adhesion to human intestinal Caco-2 epithelial cells. Immunization of mice with folded, full-length, purified SadA elicited an IgG response which provided limited protection against bacterial challenge. When anti-SadA IgG titers were enhanced by administering alum-precipitated protein, a modest additional protection was afforded. Therefore, despite SadA having pleiotropic functions, it is not a dominant, protective antigen for antibody-mediated protection against
Salmonella
.
Vaccine Immunity to Coccidioidomycosis Occurs by Early Activation of Three Signal Pathways of T Helper Cell Response (Th1, Th2, and Th17)
Authors: Hung Chiung-Yu , Gonzalez Angel , Wüthrich Marcel , Klein Bruce S. , Cole Garry T.
Published: August 2011

We have previously reported that C57BL/6 mice vaccinated with a live, attenuated mutant of
Coccidioides posadasii
, referred to as the ΔT vaccine, are fully protected against pulmonary coccidioidomycosis. This model was used here to explore the nature of vaccine immunity during the initial 2-week period after intranasal challenge. Elevated neutrophil and eosinophil infiltration into the lungs of nonvaccinated mice contrasted with markedly reduced recruitment of these cells in vaccinated animals. The numbers of lung-infiltrated macrophages and dendritic cells showed a progressive increase in vaccinated mice and corresponded with reduction of the lung infection. Concentrations of selected inflammatory cytokines and chemokines were initially higher in lung homogenates of vaccinated mice but then generally decreased at 14 days postchallenge in correlation with containment of the organism and apparent dampening of the inflammation of host tissue. Profiles of cytokines detected in lung homogenates of ΔT-vaccinated mice were indicative of a mixed T helper 1 (Th1)-, Th2-, and Th17-type immune response, a conclusion which was supported by detection of lung infiltration of activated T cells with the respective CD4
+
gamma interferon (IFN-γ)
+
, CD4
+
interleukin-5 (IL-5)
+
, and CD4
+
IL-17A
+
phenotypes. While Th1 and Th2 immunity was separately dispensed of by genetic manipulation without loss of ΔT vaccine-mediated protection, loss of functional Th17 cells resulted in increased susceptibility to infection in immunized mice. Characterization of the early events of protective immunity to
Coccidioides
infection in vaccinated mice contributes to the identification of surrogates of immune defense and provides potential insights into the design of immunotherapeutic protocols for treatment of coccidioidomycosis.
QUANTUM f-DIVERGENCES AND ERROR CORRECTION
Authors: HIAI FUMIO , MOSONYI MILÁN , PETZ DÉNES , BÉNY CÉDRIC
Published: August 2011

Quantum f-divergences are a quantum generalization of the classical notion of f-divergences, and are a special case of Petz' quasi-entropies. Many well-known distinguishability measures of quantum states are given by, or derived from, f-divergences. Special examples include the quantum relative entropy, the Rényi relative entropies, and the Chernoff and Hoeffding measures. Here we show that the quantum f-divergences are monotonic under substochastic maps whenever the defining function is operator convex. This extends and unifies all previously known monotonicity results for this class of distinguishability measures. We also analyze the case where the monotonicity inequality holds with equality, and extend Petz' reversibility theorem for a large class of f-divergences and other distinguishability measures. We apply our findings to the problem of quantum error correction, and show that if a stochastic map preserves the pairwise distinguishability on a set of states, as measured by a suitable f-divergence, then its action can be reversed on that set by another stochastic map that can be constructed from the original one in a canonical way. We also provide an integral representation for operator convex functions on the positive half-line, which is the main ingredient in extending previously known results on the monotonicity inequality and the case of equality. We also consider some special cases where the convexity of f is sufficient for the monotonicity, and obtain the inverse Hölder inequality for operators as an application. The presentation is completely self-contained and requires only standard knowledge of matrix analysis.
HERMITIAN COMPLEXITY OF REAL POLYNOMIAL IDEALS
Authors: D'ANGELO JOHN P. , PUTINAR MIHAI
Published: August 2011

We define the Hermitian complexity of a real polynomial ideal and of a real algebraic subset of Cn. This concept is aimed at determining precise necessary conditions for a Hermitian symmetric polynomial to agree with a Hermitian squared norm on an algebraic set. The latter topic has been a central theme in modern polynomial optimization and in complex geometry, specifically related to the holomorphic embedding of pseudoconvex domain into balls, or the classification of proper holomorphic maps between balls.
MODELING OF BIFURCATION PHENOMENA IN SUDDENLY EXPANDED FLOWS WITH A NEW FINITE VOLUME LATTICE BOLTZMANN METHOD
Authors: ZARGHAMI AHAD , MAGHREBI MOHAMMAD JAVAD , UBERTINI STEFANO , SUCCI SAURO
Published: August 2011

A lattice Boltzmann model using upstream finite volume scheme has been employed in the investigation of bifurcation and transition of flow through suddenly-expanded channels. To enhance the stability and accuracy of simulation, a fifth-order Runge–Kutta method is used for the time-marching and upwind biasing factors based on pressure are used as flux correctors in the lattice Boltzmann equation. In the range of Reynolds numbers investigated, the laminar flow through the expansion underwent a symmetry-breaking bifurcation. The critical Reynolds number evaluated from the experiments and the simulations were compared to other values reported in the literature. Comparisons are found to be quantitatively accurate. Furthermore, the results show that the critical Reynolds number decreases with increasing channel expansion ratio. At a fixed supercritical Reynolds number, the location at which the jet first impinges on the channel wall grows with the expansion ratio.
PROBING THE QGP PHASE BOUNDARY WITH THERMAL PROPERTIES OF ϕ MESONS
Authors: SAHOO RAGHUNATH , NAYAK TAPAN K. , ALAM JAN-E , NANDI BASANTA K. , KABANA SONJA
Published: August 2011

A novel attempt has been made to probe the QCD phase boundary by using the experimental data for transverse momenta of ϕ mesons produced in nuclear collisions at AGS, SPS and RHIC energies. The data are confronted with simple thermodynamic expectations and lattice QCD results. The experimental data indicate a first-order phase transition, with a mixed phase stretching the energy density between ~1 and 3.2 GeV/fm3 corresponding to SPS energies.
TIME SERIES FORECASTING. A COMPARATIVE STUDY BETWEEN AN EVOLVING ARTIFICIAL NEURAL NETWORKS SYSTEM AND STATISTICAL METHODS
Authors: DONATE JUAN PERALTA , SANCHEZ GERMAN GUTIERREZ , DE MIGUEL ARACELI SANCHIS
Published: August 2011

Accurate time series forecasting are important for displaying the manner in which the past continues to affect the future and for planning our day to-day activities. In recent years, a large literature has evolved on the use of evolving artificial neural networks (EANN) in many forecasting applications. Evolving neural networks are particularly appealing because of their ability to model an unspecified non-linear relationship between time series variables. In this work, a new approach of a previous Automatic Design of Artificial Neural Networks (ADANN) system applied to forecast time series is tackled. The automatic process to design artificial neural networks is carried out by a genetic algorithm (GA). These new methods, in order to get an accurate forecasting, are related with: shuffling training and validation patterns obtained from time series values and trying to improve the fitness function used in the global learning process (i.e. GA) using a new patterns set called validation II apart of the two used till the moment (i.e. training and validation). The object of this study is to try to improve the final forecasting getting an accurate system. In this paper, we also compare the forecasting ability of the ARIMA approach, evolving artificial neural networks (ADANN), unobserved components model (UCM) and a forecasting tool called Forecast Pro software using six benchmark time series.
ROBUSTIFICATION OF CHAOS IN 2D MAPS
Authors: ZERAOULIA ELHADJ , SPROTT J. C.
Published: August 2011

Robust chaos is defined as the absence of periodic windows and coexisting attractors in some neighborhood of the parameter space since the existence of such windows in the chaotic region implies fragility of the chaos. In this paper, we introduce a new terminology called robustification of chaos, which means creating robust chaos (in the sense of the above definition) in a dynamical system. As a first step, a new chaotification (robustification) method to generate robust chaos in planar maps is presented using simple piecewise smooth feedback to create a border collision bifurcation in the resulting system under some realizable conditions. The results are applied to an elementary example to illustrate the validity of the proposed method.
Steric bulkiness of pyrrole substituents and the out-of-plane deformations of porphyrins: nickel(II) octaisopropylporphyrin and its meso-nitro derivative
Authors: Haddad Raid , Lu Yi , Quirke J. Martin E. , Berget Patrick , Sun Lisong , Fettinger James C. , Leung Kevin , Qiu Yan , Schore Neil E. , van Swol Frank , Medforth Craig J. , Shelnutt John A.
Published: August 2011

Sterically bulky substituents at the β-carbons of the pyrrole rings of porphyrins are sufficient to cause large out-of-plane porphyrin distortions even in the absence of substituent groups at the meso carbons. It is well established that substituents at the meso-positions only or at both the β-pyrrole and the meso-positions are sufficiently bulky to result in large non-planar distortions of the macrocycle. However, no systematic studies of the effects of bulky β-pyrrole substituents alone have been reported. Herein, molecular simulations and X-ray crystallography of nickel(II) 2,3,7,8,12,13,17,18-octa(isopropyl)porphyrin reveal that large out-of-plane distortions (>1.5 Å) are induced by the steric repulsion of the β-isopropyl groups but fail to lead to a single strongly energetically favored conformer. The molecular simulations indicate that multiple conformers differing in the orientation of the isopropyl groups and the macrocycle conformation coexist in solution and this is confirmed by resonance Raman spectroscopy. Large downshifts in the structure-sensitive lines result from the non-planar distortion, and line broadenings result from structural heterogeneity. The heterogeneity originates from tradeoffs between energy contributions from steric repulsion and macrocycle distortion. Simulations for 5-nitro-2,3,7,8,12,13,17,18-octa(isopropyl)porphyrin suggest two possible orientations of the nitro group with respect to the macrocycle mean plane — one nearly vertical (as in the crystal structure) and another that is nearly parallel. INDO/S semiempirical calculations indicate an orbital of the NO2 group resides between the porphyrin frontier orbitals with significant mixing of the nitro and porphyrin orbitals.KEYWORDS: porphyrin, non-planar, resonance Raman, X-ray crystallography, crystal structure, isopropyl, nitro, conformer, molecular mechanics, molecular simulations, density functional theory, steric crowding, conformational heterogeneity.
NRQCD FACTORIZATION AND QUARKONIUM PRODUCTION AT HADRON-HADRON AND ep COLLIDERS
Authors: BODWIN GEOFFREY T.
Published: August 2011

I review the NRQCD factorization approach for quarkonium production and compare its predictions with measurements in hadron-hadron and ep collisions.
THE X(3872) AND OTHER X,Y,Z RESONANCES AS HIDDEN CHARM MESON-MESON MOLECULES
Authors: OSET E. , GAMERMANN D. , MOLINA R. , NIEVES J.M. , RUIZ ARRIOLA E. , BRANZ T. , LIANG WEI HONG
Published: August 2011

We report on some ideas concerning the nature of the X(3872) resonance and the need for approximately equal charged and neutral components of [Formula: see text]. Then we discuss how some hidden charm states are obtained from the interaction between vector mesons with charm and can be associated to some of the charmonium-like X,Y,Z states. Finally we discuss how the nature of these states could be investigated through different types of radiative decay.
THEORETICAL REVIEW ON HADRONIC D/Ds DECAYS
Authors: CHENG HAI-YANG
Published: August 2011

A brief review on the theoretical status of hadronic charm decays is presented. We emphasize the analyses based on the diagrammatic approach and the connection of weak annihilation with final-state rescattering. The topics on the [Formula: see text] mixing and the baryonic charm decay [Formula: see text] are sketched.
Ds DALITZ PLOT ANALYSES FROM THE B-FACTORIES
Authors:   on behalf of the BABAR Collaboration, CONVERY MARK
Published: August 2011

The resonant sub-structure of three-body charm meson decays can be effectively studied with Dalitz plot analyses. By using coherent sums of amplitudes, interference between different intermediate states can be described. Such interference effects can yield information on states, such as the scalar resonances, that is difficult to obtain in other ways. In this summary, we report on BABAR collaboration Dalitz plot analyses of two modes: [Formula: see text] and [Formula: see text].
CHARM HADRONIC DECAYS FROM FOCUS: LESSONS LEARNT
Authors: BIANCO STEFANO , PEDRINI DANIELE , REIS ALBERTO
Published: August 2011

The FOCUS photoproduction experiment took data in the ninenties and produced a wealth of results in charm physics. Some of the studies were seminal for contemporary experiments, and even paved the way for the technology of many charm and beauty analysis tools.
SEMILEPTONIC AND RARE D AND Ds CHARM DECAYS AT FOCUS
Authors:   for the FOCUS collaboration, JOHNS WILL E.
Published: August 2011

Over 1 million charm decays were collected by the E831 photoproduction experiment (FOCUS) during the 1996–1997 Fermilab fixed target run. Analysis techniques and results particular to semileptonic and rare D and Ds charm decays from the FOCUS experiment are reviewed.
CKM FITS AND THE ROLE OF CHARM DECAYS
Authors:   on behalf of the CKMfitter group, DESCOTES-GENON SÉBASTIEN
Published: August 2011

I review the role of charm decays in the determination of the structure of the CKM matrix within the Standard Model, focusing on γ,|Vcd| and |Vcs|. In addition, I illustrate how these decays can be used to constrain some New Physics scenario, taking as an example the Two Higgs-Doublet Model of type II.
CP VIOLATION AND MIXING IN CHARM MESON DECAYS FROM BABAR
Authors: CHEN CHUNHUI
Published: August 2011

Mixing and CP violation in charm meson decays provide a unique probe of possible physics beyond the standard model. In this paper, we give a brief review of the current measurements from the BABAR experiment.
THE THEORETICAL REVIEW OF EXCITED D/Ds MESONS
Authors: LIU XIANG
Published: August 2011

More and more new charmed-strange and charmed states have been observed by experiment in the past several years. In this talk, we give a brief review of the theoretical progress of excited D/Ds mesons.
CHARM SPECTROSCOPY FROM B FACTORIES
Authors:   on behalf of the BABAR collaboration, BENITEZ J.
Published: August 2011

A brief review of the excited Ds and D mesons is presented. A precision measurement of the Ds1(2536) mass and width parameters is reported by BABAR. Finally, a recent BABAR study of the Dπ and D*π final states shows first observations of the radial excitations of the D0, D*0, and D*+, as well as the L = 2 excited states of the D0 and D+, where L is the orbital angular momentum of the quarks.
DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males
Authors: Glorioso Nicola , Herrera Victoria L. M. , Didishvili Tamara , Argiolas Giuseppe , Troffa Chiara , Bulla Patrizia , Bulla Emanuela , Ruiz-Opazo Nelson
Published: August 2011

Essential hypertension is highly prevalent in the elderly population, exceeding 70% in people older than 60 yr of age, and remains a leading risk factor for heart disease, stroke, and chronic renal disease. Elucidation of genetic determinants is critical but remains a challenge due to its complex, multifactorial pathogenesis. We investigated the role DEspR promoter variants, previously associated with male essential hypertension susceptibility, in blood pressure (BP) regulation. We detected a single nucleotide polymorphism within the DEspR 5′-regulatory region associated with increased BP in a male Sardinian cohort accounting for 11.0 mmHg of systolic BP ( P < 10−15) and 9.3 mmHg of diastolic BP ( P < 10−15). Sequence analysis of three normotensive subjects homozygous for the rs6535847 “normotension-associated T-allele” identified a canonical TATAAAA-box in contrast to a CATAAAA-motif in three hypertensive subjects homozygous for the rs6535847 “hypertension-associated C-allele.” In vitro analysis detected decreased transcription activity with the CATAAAA-motif promoter-construct compared with the canonical TATAAAA-box promoter-construct. Although BP did not differ between DEspR+/− knockout male mice and wild-type littermates at 6 mo of age, radiotelemetric BP measurements in 18 mo old inbred DEspR+/− knockout male mice known to have decreased DEspR RNA and protein detected higher systolic, mean, and diastolic BPs in DEspR+/− mice compared with littermate wild-type controls ( P < 0.05). Our results demonstrate that promoter variants in DEspR associated with hypertension susceptibility and increased BP in Sardinian males affect transcription levels, which then affect BP in an age-dependent and male-specific manner. This finding is concordant with the late-onset and sex-specific characteristics of essential hypertension, thus reiterating the mandate for sex-specific analyses and treatment approaches for essential hypertension.
Almost Surely Asymptotic Stability of Exact and Numerical Solutions for Neutral Stochastic Pantograph Equations
Authors: Yu Zhanhua
Published: August 2011

We study the almost surely asymptotic stability of exact solutions to neutral stochastic pantograph equations (NSPEs), and sufficient conditions are obtained. Based on these sufficient conditions, we show that the backward Euler method (BEM) with variable stepsize can preserve the almost surely asymptotic stability. Numerical examples are demonstrated for illustration.
Mycobacterium tuberculosisComplex Genotype Diversity and Drug Resistance Profiles in a Pediatric Population in Mexico
Authors: Macías Parra Mercedes , Kumate Rodríguez Jesús , Arredondo García José Luís , López-Vidal Yolanda , Castañón-Arreola Mauricio , Balandrano Susana , Rastogi Nalin , Gutiérrez Castrellón Pedro
Published: August 2011

The aim of this study was to determine the frequency of drug resistance and the clonality of genotype patterns inM. tuberculosisclinical isolates from pediatric patients in Mexico (n=90patients from 19 states; time period—January 2002 to December 2003). Pulmonary disease was the most frequent clinical manifestation (71%). Children with systemic tuberculosis (TB) were significantly younger compared to patients with localized TB infections (mean7.7±6.2years versus15±3.4yearsP=0.001). Resistance to any anti-TB drug was detected in 24/90 (26.7%) of the isolates; 21/90 (23.3%) and 10/90 (11.1%) were resistant to Isoniazid and Rifampicin, respectively, and 10/90 (11.1%) strains were multidrug-resistant (MDR). Spoligotyping produced a total of 55 different patterns; 12/55 corresponded to clustered isolates (n=47, clustering rate of 52.2%), and 43/55 to unclustered isolates (19 patterns were designated as orphan by the SITVIT2 database). Database comparison led to designation of 36 shared types (SITs); 32 SITs (n=65isolates) matched a preexisting shared type in SITVIT2, whereas 4 SITs (n=6isolates) were newly created. Lineage classification based on principal genetic groups (PGG) revealed that 10% of the strains belonged to PGG1 (Bovis and Manu lineages). Among PGG2/3 group, the most predominant clade was the Latin-American and Mediterranean (LAM) in 27.8% of isolates, followed by Haarlem and T lineages. The number of single drug-resistant (DR) and multidrug-resistant (MDR-TB) isolates in this study was similar to previously reported in studies from adult population with risk factors. No association between the spoligotype, age, region, or resistance pattern was observed. However, contrary to a study onM. tuberculosisspoligotyping in Acapulco city that characterized a single cluster of SIT19 corresponding to the EAI2-Manila lineage in 70 (26%) of patients, not a single SIT19 isolate was found in our pediatric patient population. Neither did we find any shared type belonging to the EAI family which represents ancestral PGG1 strains within theM. tuberculosiscomplex. We conclude that the population structure of pediatric TB in our setting is different from the one prevailing in adult TB patient population of Guerrero.
Missing‐Values Adjustment for Mixed‐Type Data
Authors: Tarsitano Agostino , Falcone Marianna
Published: August 2011

We propose a new method of single imputation, reconstruction, and estimation of nonreported, incorrect, implausible, or excluded values in more than one field of the record. In particular, we will be concerned with
data sets involving a mixture of numeric, ordinal, binary, and categorical variables. Our technique is a variation of the popular nearest neighbor hot deck imputation (NNHDI) where “nearest” is defined in terms of a global distance obtained as a convex combination of the distance matrices computed for the various types of variables. We address the problem of proper weighting of the partial distance matrices in order to reflect their significance, reliability, and statistical adequacy. Performance of several weighting schemes is compared under a variety of settings in coordination with imputation of the least power mean of the Box‐Cox transformation applied to the values of the donors. Through analysis of simulated and actual data sets, we will show that this approach is appropriate. Our main contribution has been to demonstrate that mixed data may optimally be combined to allow the accurate reconstruction of missing values in the target variable even when some data are absent from the other fields of the record.
Personality Profiles Identify Depressive Symptoms over Ten Years? A Population-Based Study
Authors: Josefsson Kim , Merjonen Päivi , Jokela Markus , Pulkki-Råback Laura , Keltikangas-Järvinen Liisa
Published: August 2011

Little is known about the relationship between temperament and character inventory (TCI) profiles and depressive symptoms. Personality profiles are useful, because personality traits may have different effects on depressive symptoms when combined with different combinations of other traits. Participants were from the population-based Young Finns study with repeated measurements in 1997, 2001, and 2007 ( to 1902). TCI was administered in 1997 and mild depressive symptoms (modified Beck’s depression inventory, BDI) were reported in 1997, 2001, and 2007. BDI-II was also administered in 2007. We found that high harm avoidance and low self-directedness related strongly to depressive symptoms. In addition, sensitive (NHR) and fanatical people (ScT) were especially vulnerable to depressive symptoms. high novelty seeking and reward dependence increased depressive symptoms when harm avoidance was high. These associations were very similar in cross-sectional and longitudinal analysis. Personality profiles help in understanding the complex associations between depressive symptoms and personality.
A Window into the Heterogeneity of Human Cerebrospinal Fluid Aβ Peptides
Authors: Ghidoni Roberta , Paterlini Anna , Albertini Valentina , Stoppani Elena , Binetti Giuliano , Fuxe Kjell , Benussi Luisa , Agnati Luigi F.
Published: August 2011

The initiating event in Alzheimer′s disease (AD) is an imbalance in the production and clearance of amyloid beta (Aβ) peptides leading to the formation of neurotoxic brain Aβ assemblies. Cerebrospinal Fluid (CSF), which is a continuum of the brain, is an obvious source of markers reflecting central neuropathologic features of brain diseases. In this review, we provide an overview and update on our current understanding of the pathobiology of human CSF Aβ peptides. Specifically, we focused our attention on the heterogeneity of the CSF Aβ world discussing (1) basic research studies and what has been translated to clinical practice, (2) monomers and other soluble circulating Aβ assemblies, and (3) communication modes for Aβ peptides and their microenvironment targets. Finally, we suggest that Aβ peptides as well as other key signals in the central nervous system (CNS), mainly involved in learning and hence plasticity, may have a double‐edged sword action on neuron survival and function.
Local Exponential Regulation of Nonholonomic Systems in Approximate Chained Form with Applications to Off-Axle Tractor-Trailers
Authors: Ma Bao-Li
Published: August 2011

Most of drift-less nonholonomic systems cannot be exactly converted to an nonholonomic chained form, a wealth of design tools developed for the control of nonholonomic chained form are thus not directly applicable to such systems. Nevertheless, there exists a class of systems that may be locally approximated by the nonholonomic chained form around certain equilibrium points. In this work, we propose a discontinuous and a smooth time-varying control laws respectively for the approximated nonholonomic chained form, guaranteeing local exponential convergence of state to the desired equilibrium point. An tractor towing off-axle trailers is taken as an example to illustrate the approaches.
Regulator of G Protein Signaling 6 Mediates Doxorubicin-Induced ATM and p53 Activation by a Reactive Oxygen Species–Dependent Mechanism
Authors: Huang Jie , Yang Jianqi , Maity Biswanath , Mayuzumi Daisuke , Fisher Rory A.
Published: August 2011

Doxorubicin (DXR), among the most widely used cancer chemotherapy agents, promotes cancer cell death via activation of ataxia telangiectasia mutated (ATM) and the resultant upregulation of tumor suppressor p53. The exact mechanism by which DXR activates ATM is not fully understood. Here, we discovered a novel role for regulator of G protein signaling 6 (RGS6) in mediating activation of ATM and p53 by DXR. RGS6 was robustly induced by DXR, and genetic loss of RGS6 dramatically impaired DXR-induced activation of ATM and p53, as well as its in vivo apoptotic actions in heart. The ability of RGS6 to promote p53 activation in response to DXR was independent of RGS6 interaction with G proteins but required ATM. RGS6 mediated activation of ATM and p53 by DXR via a reactive oxygen species (ROS)-dependent and DNA damage–independent mechanism. This mechanism represents the primary means by which DXR promotes activation of the ATM–p53 apoptosis pathway that underlies its cytotoxic activity. Our findings contradict the canonical theories that DXR activates ATM primarily by promoting DNA damage either directly or indirectly (via ROS) and that RGS6 function is mediated by its interactions with G proteins. These findings reveal a new mechanism for the chemotherapeutic actions of DXR and identify RGS6 as a novel target for cancer chemotherapy. Cancer Res; 71(20); 6310–9. ©2011 AACR.
Evolution of Tumor Invasiveness: The Adaptive Tumor Microenvironment Landscape Model
Authors: Lee Hyung-Ok , Silva Ariosto S. , Concilio Susanna , Li Yue-Sheng , Slifker Michael , Gatenby Robert A. , Cheng Jonathan D.
Published: August 2011

Interactions between cancer cells and their microenvironment are crucial for promoting tumor growth and invasiveness. In the tumor adaptive landscape model, hypoxic and acidic microenvironmental conditions reduce the fitness of cancer cells and significantly restrict their proliferation. This selects for enhanced motility as cancer cells may evolve an invasive phenotype if the consequent cell movement is rewarded by proliferation. Here, we used an integrative approach combining a mathematical tumor adaptive landscape model with experimental studies to examine the evolutionary dynamics that promote an invasive cancer phenotype. Computer simulation results hypothesized an explicit coupling of motility and proliferation in cancer cells. The mathematical modeling results were also experimentally examined by selecting Panc-1 cells with enhanced motility on a fibroblast-derived 3-dimensional matrix for cells that move away from the unfavorable metabolic constraints. After multiple rounds of selection, the cells that adapted through increased motility were characterized for their phenotypic properties compared with stationary cells. Microarray and gene depletion studies showed the role of Rho-GDI2 in regulating both cell movement and proliferation. Together, this work illustrates the partnership between evolutionary mathematical modeling and experimental validation as a potentially useful approach to study the complex dynamics of the tumor microenvironment. Cancer Res; 71(20); 6327–37. ©2011 AACR.
Eribulin Mesylate
Authors: Jain Sarika , Vahdat Linda T.
Published: August 2011

Eribulin mesylate, a nontaxane, completely synthetic microtubule inhibitor, has recently been approved by the U.S. Food and Drug Administration as third-line treatment of metastatic breast cancer refractory to anthracyclines and taxanes. Eribulin is a synthetic analogue of halichondrin B, which inhibits microtubule polymerization by a mechanism distinct from other available antitubulin agents. Eribulin significantly increased overall survival (OS; median OS for the eribulin-treated group was 13.1 months versus 10.6 months for the group treated by investigator's choice) in a heavily pretreated metastatic breast cancer population. Eribulin has a manageable side-effect profile, notably neutropenia and fatigue, and a relatively low incidence of peripheral neuropathy. The mechanism of action, pharmacokinetics, preclinical antitumor activity, and clinical trials of eribulin in the metastatic breast cancer setting are reviewed here. Clin Cancer Res; 17(21); 6615–22. ©2011 AACR.
NF-κB Is Required for Smac Mimetic-Mediated Sensitization of Glioblastoma Cells for γ-Irradiation–Induced Apoptosis
Authors: Berger Rebecca , Jennewein Claudia , Marschall Viola , Karl Sabine , Cristofanon Silvia , Wagner Liane , Vellanki Sri HariKrishna , Hehlgans Stephanie , Rödel Franz , Debatin Klaus-Michael , Ludolph Albert C. , Fulda Simone
Published: August 2011

Evasion of apoptosis contributes to radioresistance of glioblastoma, calling for novel strategies to overcome apoptosis resistance. In this study, we investigated the potential of the small molecule Smac mimetic BV6 to modulate radiosensitivity of glioblastoma cells. Here, we identify a novel proapoptotic function of NF-κB in γ-irradiation–induced apoptosis of glioblastoma cells by showing, for the first time, that NF-κB is critically required for Smac mimetic–mediated radiosensitization. BV6 significantly increases γ-irradiation–triggered apoptosis in several glioblastoma cell lines in a dose- and time-dependent manner. Calculation of combination index (CI) reveals that the interaction of BV6 and γ-irradiation is highly synergistic (CI < 0.3). Molecular studies show that BV6 stimulates NF-κB activation, which is critical for radiosensitization, because genetic inhibition of NF-κB by overexpression of the dominant-negative superrepressor IκBα-SR significantly decreases BV6- and γ-irradiation–induced apoptosis. Also, the BV6-mediated enhancement of γ-irradiation–triggered caspase activation, drop of mitochondrial membrane potential, and cytochrome c release is abolished in cells overexpressing IκBα-SR. Similarly, NF-κB inhibition by ectopic expression of a kinase dead mutant of IKKβ prevents the BV6-mediated sensitization for γ-irradiation. The clinical relevance is underscored by experiments with primary tumor samples showing that BV6 sensitizes primary cultured glioma cells as well as glioblastoma-initiating cancer stem cells derived from surgical specimens for γ-irradiation. In conclusion, we identify NF-κB as a critical mediator of Smac mimetic-conferred radiosensitization of glioblastoma cells. These results have important implications for the development of Smac mimetic–based combination protocols for radiosensitization of glioblastoma. Mol Cancer Ther; 10(10); 1867–75. ©2011 AACR.
A Molecular Screening Approach to Identify and Characterize Inhibitors of Glioblastoma Stem Cells
Authors: Visnyei Koppany , Onodera Hideyuki , Damoiseaux Robert , Saigusa Kuniyasu , Petrosyan Syuzanna , De Vries David , Ferrari Denise , Saxe Jonathan , Panosyan Eduard H. , Masterman-Smith Michael , Mottahedeh Jack , Bradley Kenneth A. , Huang Jing , Sabatti Chiara , Nakano Ichiro , Kornblum Harley I.
Published: August 2011

Glioblastoma (GBM) is among the most lethal of all cancers. GBM consist of a heterogeneous population of tumor cells among which a tumor-initiating and treatment-resistant subpopulation, here termed GBM stem cells, have been identified as primary therapeutic targets. Here, we describe a high-throughput small molecule screening approach that enables the identification and characterization of chemical compounds that are effective against GBM stem cells. The paradigm uses a tissue culture model to enrich for GBM stem cells derived from human GBM resections and combines a phenotype-based screen with gene target-specific screens for compound identification. We used 31,624 small molecules from 7 chemical libraries that we characterized and ranked based on their effect on a panel of GBM stem cell-enriched cultures and their effect on the expression of a module of genes whose expression negatively correlates with clinical outcome: MELK, ASPM, TOP2A, and FOXM1b. Of the 11 compounds meeting criteria for exerting differential effects across cell types used, 4 compounds showed selectivity by inhibiting multiple GBM stem cells-enriched cultures compared with nonenriched cultures: emetine, n-arachidonoyl dopamine, n-oleoyldopamine (OLDA), and n-palmitoyl dopamine. ChemBridge compounds #5560509 and #5256360 inhibited the expression of the 4 mitotic module genes. OLDA, emetine, and compounds #5560509 and #5256360 were chosen for more detailed study and inhibited GBM stem cells in self-renewal assays in vitro and in a xenograft model in vivo. These studies show that our screening strategy provides potential candidates and a blueprint for lead compound identification in larger scale screens or screens involving other cancer types. Mol Cancer Ther; 10(10); 1818–28. ©2011 AACR.
Mitochondrial DNA Copy Number and Pancreatic Cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study
Authors: Lynch Shannon M. , Weinstein Stephanie J. , Virtamo Jarmo , Lan Qing , Liu Chin-San , Cheng Wen-Ling , Rothman Nathaniel , Albanes Demetrius , Stolzenberg-Solomon Rachael Z.
Published: August 2011

Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number. To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case–control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50 to 69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants, with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated ORs and 95% CIs using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two sided. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64, 95% CI = 1.01–2.67, continuous OR = 1.14, 95% CI 1.06–1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR = 2.14, 95% CI = 1.16–3.96, Ptrend = 0.01, continuous OR = 1.21, 95% CI = 1.10–1.33), but not for cases occurring during follow-up of 7 years or greater (OR = 1.14, 95% CI = 0.53–2.45, continuous OR = 1.05, 95% CI = 0.93–1.18). Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development. Cancer Prev Res; 4(11); 1912–9. ©2011 AACR.
Clinical Features and Long-Term Follow-Up of Quasi-Moyamoya Disease in Children
Authors: Hayashi Kentaro , Horie Nobutaka , Suyama Kazuhiko , Nagata Izumi
Published: August 2011

Background: Inherited or acquired disorders and conditions may present in conjunction with moyamoya disease. This condition is known as quasi-moyamoya disease. Methods: A retrospective review of 69 moyamoya disease patients treated for the past 20 years identified 7 patients with quasi-moyamoya disease and 5 of them were pediatric patients. Results: The mean age at initial diagnosis was 6.4 years (range 5–9). Associated disorders were: craniosynostosis, dwarfism with coarctation of aorta, Proteus syndrome, and cranial irradiation for brain tumor. Their clinical type included cerebral ischemia in 3 patients, cerebral bleeding with ischemia in 1 and epilepsy in 1. The 3 patients with cerebral ischemia underwent bypass surgery and their ischemia was improved. One patient died of brain tumor recurrence and the activities of daily living in the remaining patients were affected by mental retardation. Conclusions: The clinical course and radiological finding of quasi-moyamoya disease are diverse because of associated disorders, distinguishing definite moyamoya disease.
Unusual Case of ‘Trapped Fourth Ventricle’ in a Child with Posthemorrhagic Hydrocephalus – Lessons Learnt
Authors: Udayakumaran Suhas , Beni Adani Liana
Published: August 2011

In most of the children with posthemorrhagic hydrocephalus (PHH), multidisciplinary follow-up is performed, with the focus on consequences of prematurity, cerebral palsy (CP) and hydrocephalus. A large fourth ventricle is common in these children but imaging performed in order to document ventricles and tissue damage is not oriented to exclude coexisting rare pathologies. We report a 3-year-old child with spastic CP, secondary to prematurity and PHH. A ventriculoperitoneal shunt was inserted at the age of 2 months. On follow-up imaging the child demonstrated well-drained supratentorial ventricles with a persistent large fourth ventricle. Because of a neurological change in spasticity and new-onset torticollis, a repeat MRI was performed, suggesting a cystic, nonenhancing lesion of the fourth ventricle. The surgical exploration revealed a large dermoid of the fourth ventricle. We analyze the differential diagnosis of a clinically significant large fourth ventricle in a shunted child with PHH and CP. This includes conditions without pressure in the posterior fossa such as tissue loss due to cerebellar atrophy, or pathologies causing a true increase in pressure of the fourth ventricle (isolated fourth ventricle, cystic lesions and neoplasms of the fourth ventricle). Neurologically compromised children pose additional challenges in reaching a definitive diagnosis and hence require a careful regular assessment of their clinical status with additional well-timed imaging with appropriate protocols to allow appropriate treatment when indicated and to avoid morbidity due to delayed diagnosis. We present a rare coexistence of a dermoid tumor within the fourth ventricle in a CP child with PHH and express the dilemmas associated with its management.