bluuebunny/crossref_metadata_2025 huggingface dataset:
The cystic fibrosis transmembrane conductance regulator in reproductive health and disease
Authors: Chan Hsiao Chang , Ruan Ye Chun , He Qiong , Chen Min Hui , Chen Hui , Xu Wen Ming , Chen Wen Ying , Xie Chen , Zhang Xiao Hu , Zhou Zhen
Published: November 2008

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel regulated by cAMP‐dependent phosphorylation, which is expressed in epithelial cells of a wide variety of tissues including the reproductive tracts. Mutations in the gene encoding CFTR cause cystic fibrosis, a common genetic disease in Caucasian populations with a multitude of clinical manifestations including infertility/subfertility in both sexes. However, the physiological role of CFTR in reproduction and its involvement in the pathogenesis of reproductive diseases remain largely unknown. This review discusses the role of CFTR in regulating fluid volume and bicarbonate secretion in the reproductive tracts and their importance in various reproductive events. We also discuss the contribution of CFTR dysfunction to a number of pathological conditions. The evidence presented is consistent with an important role of CFTR in reproductive health and disease, suggesting that CFTR might be a potential target for the diagnosis and treatment of reproductive diseases including infertility.
Approximations for the period of the simple pendulum based on the arithmetic-geometric mean
Authors: Carvalhaes Claudio G. , Suppes Patrick
Published: November 2008

We use the arithmetic-geometric mean to derive approximate solutions for the period of the simple pendulum. The fast convergence of the arithmetic-geometric mean yields accurate solutions. We also discuss the invention of the pendulum clock by Christiaan Huygens in 1656–1657.
Inexpensive high-precision capacitance measurements and their applications in undergraduate laboratories
Authors: Clayhold Jeffrey , Priest Joseph
Published: November 2008

An inexpensive system for precision capacitance measurement is presented. The system is appropriate for undergraduate laboratories is based on a newly available capacitance-to-digital integrated circuit that can measure picofarad capacitances to six significant figures. The circuitry software for controlling the integrated circuit with a personal computer via an I2C interface bus are described. Examples of experiments that make use of the circuitry are discussed, including a novel hydrostatic magnetometer that uses precision capacitance measurement to determine the magnetization of a small sample.
Semiclassical scattering in two dimensions
Authors: Adhikari Sadhan K. , Hussein Mahir S.
Published: November 2008

The semiclassical limit of quantum mechanical scattering in two dimensions is developed and the Wentzel–Kramers–Brillouin and eikonal results for two-dimensional scattering is derived. No backward or forward glory scattering is present in two dimensions. Other phenomena, such as rainbows and orbiting, do occur.
Two examples of organic opto-electronic devices: Light emitting diodes and solar cells
Authors: Maldonado J. L. , Ramos-Ortíz G. , Miranda M. L. , Vázquez-Córdova S. , Meneses-Nava M. A. , Barbosa-García O. , Ortíz-Gutiérrez M.
Published: November 2008

Organic and polymeric (plastic) opto-electronic devices have been developed over the past decade, and some of them have made the leap from the research laboratory to commercial use. We present a simple and inexpensive method of fabricating organic light emitting diodes and organic photovoltaic cells. The devices are fabricated by the deposition of solid films based on the fluorescent polymer MEH:PPV using the spin-coating technique. The films were sandwiched between electrodes, one of which was made of Bi-Pb-Cd-Sn alloy. An overview of these two devices is also provided.
A free-electron calculation for quantum size effects in the properties of metallic islands on surfaces
Authors: Atkinson W. A. , Slavin A. J.
Published: November 2008

A metal film that is only a few atomic layers thick, on an appropriate substrate, creates a quantum well that confines the conduction electrons in the direction perpendicular to the film. As a result, components of the wavevector in the plane of the film are quasicontinuous, but the perpendicular component is discrete. The result is a strong oscillatory dependence of the film properties on film thickness, including the Fermi energy and the density of states. We show that these quantum effects associated with the film thickness can be understood within the free electron theory of metals. Because of its simplicity, the thin-film quantum well is appropriate as a problem for senior undergraduate and graduate students and provides an introduction to quantum size effects.
A “local observables” method for wave mechanics applied to atomic hydrogen
Authors: Bowman Peter J.
Published: November 2008

An alternative method of deriving the values of the observables of atomic systems is presented. Rather than using operators and eigenvalues the local variables method uses the continuity equation together with current densities derived from wave functions that are solutions of the Dirac or Pauli equation. The method is applied to atomic hydrogen using the usual language of quantum mechanics rather than that of geometric algebra with which the method is often associated. The picture of the atom that emerges is one in which the electron density as a whole is rotating about a central axis. The results challenge some assumptions of conventional quantum mechanics. Electron spin is shown to be a property of the dynamical motion of the electron and not an intrinsic property of the electron, the ground state of hydrogen is shown to have an orbital angular momentum of ℏ, and excited states are shown to have angular momenta that are different from the eigenvalues of the usual quantum mechanical operators. The uncertainty relations are found not to be applicable to the orthogonal components of the angular momentum. No double electron spin gyromagnetic ratio is required to account for the observed magnetic moments, and the behavior of the atom in a magnetic field is described entirely in kinetic terms.
A simple experiment to distinguish between replicated and duplicated compact discs using Fraunhofer diffraction
Authors: Fernández-Dorado José , Hernández-Andrés Javier , Valero Eva M. , Nieves Juan L. , Romero Javier
Published: November 2008

Compact discs are a useful tool for studying interference and diffraction. We propose an easy and inexpensive experiment to distinguish between replicated and duplicated compact discs based on Fraunhofer diffraction. The nonvisible differences of the surface of compact discs depend on the way that they have been manufactured and can be seen by using a laser beam in a simple diffraction experiment. The method has been tested on many different brands of CDs and is reliable.
Experimental high Reynolds number turbulence with an active grid
Authors: Mordant Nicolas
Published: November 2008

This article describes the wind tunnel used in the Physics Department of the Ecole Normale Supérieure in Paris for undergraduate laboratory courses. By using an active grid, which consists of a grid of shafts fitted with randomly rotating wings, a fully turbulent flow is observed. The velocity of the air flow is measured with a low cost hot wire probe. The Reynolds number is large enough so that predictions of the 1941 Kolmogorov theory of turbulence can be observed, such as the famous k−5∕3 spectrum, in spite of the small size of the tunnel. Deviations from the Kolmogorov theory are also observed and quantified. The moderate cost and size of the wind tunnel due to the use of the active grid make it a valuable teaching tool for introducing the phenomenology of turbulence to undergraduates.
The evolution of free wave packets
Authors: Andrews Mark
Published: November 2008

We discuss four general features of the force-free evolution of wave packets: (1) The spatial spread of a packet changes with time in a simple way. (2) For sufficiently short durations (related to the spread in the momentum of the packet) the probability distribution will move with uniform speed and little change in shape. (3) After a sufficiently long time (related to the initial spatial spread) the wave function converges to a simple form that is simply related to the momentum distribution of the packet. In this asymptotic regime the shape of the probability distribution no longer changes, and its scale increases linearly with the time. (4) There is an infinite denumerable set of simple wave packets (the Hermite-Gauss packets) that do not change shape at any time during their evolution.
A velocity-dependent potential of a rigid body in a rotating frame
Authors: Moreno G. A. , Barrachina R. O.
Published: November 2008

We derive a velocity-dependent potential for describing the dynamics of a rigid body in a rotating frame. We show that, as for one-particle systems, the different components of this potential can be associated with electromagnetic analogs. We provide some examples to demonstrate the feasibility of using the potential as an alternative description of rigid body problems.
A statistical mechanics model for free-for-all airplane passenger boarding
Authors: Steffen Jason H.
Published: November 2008

I discuss a model for free-for-all passenger boarding which is employed by some discount air carriers. The model is based on the principles of statistical mechanics, where each seat in the aircraft has an associated energy which reflects the preferences of travelers. As each passenger enters the airplane they select their seats using Boltzmann statistics, proceed to that location, load their luggage, sit down, and the partition function seen by remaining passengers is modified to reflect this fact. I discuss the various model parameters and make qualitative comparisons of this passenger boarding model with those that involve assigned seats. The model can be used to predict the probability that certain seats will be occupied at different times during the boarding process. These results might provide a useful description of this boarding method. The model is a relatively unusual application of undergraduate level physics and describes a situation familiar to many students and faculty.
Modeling theory applied: Modeling Instruction in introductory physics
Authors: Brewe Eric
Published: November 2008

Modeling Instruction is a pedagogical approach which has been widely and successfully employed in high school physics instruction but is not commonly used at the university level. The goal of this paper is to describe the nature of Modeling Instruction at the university level and to clarify the role of models in physics instruction. A university physics class is described as it progresses through a typical modeling cycle, Introduction and Representation, Coordination of Representations, Abstraction and Generalization, and Application and Refinement. The benefits of modeling instruction are discussed.
Antileishmanial Activity of 1,3,4-Thiadiazolium-2-Aminide in Mice Infected withLeishmania amazonensis
Authors: Rodrigues Raquel F. , Charret Karen S. , da Silva Edson F. , Echevarria Áurea , Amaral Verônica F. , Leon Leonor L. , Canto-Cavalheiro Marilene M.
Published: November 2008

The efficacy of two mesoionic derivatives (MI-H-H and MI-4-OCH3) was evaluated in CBA/J mice infected withLeishmania amazonensis. Treatment with these compounds demonstrated that the MI-4-OCH3derivative and the reference drug meglumine antimoniate (Glucantime) presented significant activity relative to an untreated control. No apparent hepatic or renal toxicity due to these mesoionic compounds was found.
Inhibition of Methionyl-tRNA Synthetase by REP8839 and Effects of Resistance Mutations on Enzyme Activity
Authors: Green Louis S. , Bullard James M. , Ribble Wendy , Dean Frank , Ayers David F. , Ochsner Urs A. , Janjic Nebojsa , Jarvis Thale C.
Published: November 2008

REP8839 is a selective inhibitor of methionyl-tRNA synthetase (MetRS) with antibacterial activity against a variety of gram-positive organisms. We determined REP8839 potency against
Staphylococcus aureus
MetRS and assessed its selectivity for bacterial versus human orthologs of MetRS. The inhibition constant (

K
i

) of REP8839 was 10 pM for
Staphylococcus aureus
MetRS. Inhibition of MetRS by REP8839 was competitive with methionine and uncompetitive with ATP. Thus, high physiological ATP levels would actually facilitate optimal binding of the inhibitor. While many gram-positive bacteria, such as
Staphylococcus aureus
, express exclusively the MetRS1 subtype, many gram-negative bacteria express an alternative homolog called MetRS2. Some gram-positive bacteria, such as
Streptococcus pneumoniae
and
Bacillus anthracis
, express both MetRS1 and MetRS2. MetRS2 orthologs were considerably less susceptible to REP8839 inhibition. REP8839 inhibition of human mitochondrial MetRS was 1,000-fold weaker than inhibition of
Staphylococcus aureus
MetRS; inhibition of human cytoplasmic MetRS was not detectable, corresponding to >1,000,000-fold selectivity for the bacterial target relative to its cytoplasmic counterpart. Mutations in MetRS that confer reduced susceptibility to REP8839 were examined. The mutant MetRS enzymes generally exhibited substantially impaired catalytic activity, particularly in aminoacylation turnover rates. REP8839

K
i

values ranged from 4- to 190,000-fold higher for the mutant enzymes than for wild-type MetRS. These observations provide a potential mechanistic explanation for the reduced growth fitness observed with MetRS mutant strains relative to that with wild-type
Staphylococcus aureus
.
Interaction Studies of Tipranavir-Ritonavir with Clarithromycin, Fluconazole, and Rifabutin in Healthy Volunteers
Authors: la Porte Charles J. L. , Sabo John P. , Elgadi Mabrouk , Cameron D. William
Published: November 2008

Three separate controlled, two-period studies with healthy volunteers assessed the pharmacokinetic interactions between tipranavir-ritonavir (TPV/r) in a 500/200-mg dose and 500 mg of clarithromycin (CLR), 100 mg of fluconazole (FCZ), or 150 mg of rifabutin (RFB). The CLR study was conducted with 24 subjects. The geometric mean ratios (GMR) and 90% confidence intervals (90% CI; given in parentheses) of the areas under the concentration-time curve (AUC), the maximum concentrations of the drugs in serum (
C
max
), and the concentrations in serum at 12 h postdose (Cp12h) for multiple-dose TPV/r and multiple-dose CLR, indicating the effect of TPV/r on the CLR parameters, were 1.19 (1.04-1.37), 0.95 (0.83-1.09), and 1.68 (1.42-1.98), respectively. The formation of the metabolite 14-OH-CLR was decreased by 95% in the presence of TPV, and the TPV AUC increased 66% compared to that for human immunodeficiency virus (HIV)-negative historical controls. The FCZ study was conducted with 20 subjects. The GMR (and 90% CI) of the AUC,
C
max
, and Cp24h, indicating the effect of multiple-dose TPV/r on the multiple-dose FCZ parameters, were 0.92 (0.88-0.95), 0.94 (0.91-0.98), and 0.89 (0.85-0.92), respectively. The TPV AUC increased by 50% compared to that for HIV-negative historical controls. The RFB study was conducted with 24 subjects. The GMR (and 90% CI) of the AUC,
C
max
, and Cp12h for multiple-dose TPV/r and single-dose RFB, indicating the effect of TPV/r on the RFB parameters, were 2.90 (2.59-3.26), 1.70 (1.49-1.94), and 2.14 (1.90-2.41), respectively. The GMR (and 90% CI) of the AUC,
C
max
, and Cp12h of TPV/r and RFB with 25-
O
-desacetyl-RFB were 4.33 (3.86-4.86), 1.86 (1.63-2.12), and 2.76 (2.44-3.12), respectively. Coadministration of TPV with a single dose of RFB resulted in a 16% increase in the TPV Cp12h compared to that for TPV alone. In the general population, no dose adjustments are necessary for the combination of TPV/r and CLR or FCZ. Combining TPV/r with RFB should be done with caution, while toxicity and RFB drug levels should be monitored. Study medications were generally well-tolerated in these studies.
Compounds Structurally Related to Ellagic Acid Show Improved Antiplasmodial Activity
Authors: Sturm Nicole , Hu Ying , Zimmermann Herbert , Fritz-Wolf Karin , Wittlin Sergio , Rahlfs Stefan , Becker Katja
Published: November 2008

The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione
S
-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of
Plasmodium falciparum
GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of
P. falciparum
GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of
Plasmodium
revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant
P. falciparum
strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In
Plasmodium
, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of
Plasmodium berghei
-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
Statistical Model To Evaluate In Vivo Activities of Antimalarial Drugs in a
Plasmodium cynomolgi
-Macaque Model for
Plasmodium vivax
Malaria
Authors: Kocken Clemens H. M. , Remarque Edmond J. , Dubbeld Martin A. , Wein Sharon , van der Wel Annemarie , Verburgh R. Joyce , Vial Henri J. , Thomas Alan W.
Published: November 2008

Preclinical animal models informing antimalarial drug development are scarce. We have used asexual erythrocytic
Plasmodium cynomolgi
infections of rhesus macaques to model
Plasmodium vivax
during preclinical development of compounds targeting parasite phospholipid synthesis. Using this malaria model, we accumulated data confirming highly reproducible infection patterns, with self-curing parasite peaks reproducibly preceding recrudescence peaks. We applied nonlinear mixed-effect (NLME) models, estimating treatment effects in three drug studies: G25 (injected) and the bisthiazolium prodrugs TE4gt and TE3 (oral). All compounds fully cured
P. cynomolgi
-infected macaques, with significant effects on parasitemia height and time of peak. Although all three TE3 doses tested were fully curative, NLME models discriminated dose-dependent differential pharmacological antimalarial activity. By applying NLME modeling treatment effects are readily quantified. Such drug development studies are more informative and contribute to reduction and refinement in animal experimentation.
A Small-Molecule Screen Identifies the Antipsychotic Drug Pimozide as an Inhibitor ofListeria monocytogenesInfection
Authors: Lieberman Linda A. , Higgins Darren E.
Published: November 2008

We developed a screening procedure to identify small-molecule compounds that altered infection byListeria monocytogenesto gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered theL. monocytogenesinfection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape ofL. monocytogenesin BMM. The inhibitory effect of pimozide on internalization was not specific forL. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis,Salmonella entericaserovar Typhimurium, andEscherichia coliK12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread ofL. monocytogenesduring the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide onL. monocytogenesinfection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
Phenotypic and Enzymatic Comparative Analysis of the Novel KPC Variant KPC-5 and Its Evolutionary Variants, KPC-2 and KPC-4
Authors: Wolter Daniel J. , Kurpiel Philip M. , Woodford Neil , Palepou Marie-France I. , Goering Richard V. , Hanson Nancy D.
Published: November 2008

A novel
Klebsiella pneumoniae
carbapenemase (KPC) variant, designated
bla
KPC-5
, was discovered in a carbapenem-resistant
Pseudomonas aeruginosa
clinical isolate from Puerto Rico. Characterization of the upstream region of
bla
KPC-5
showed significant differences from the flanking regions of other
bla
KPC
variants. Comparison of amino acid sequences with those of other KPC enzymes revealed that KPC-5 was an intermediate between KPC-2 and KPC-4, differing from KPC-2 by a single amino acid substitution (Pro
103
→Arg), while KPC-4 contained Pro
103
→Arg plus an additional amino acid change (Val
239
→Gly). Transformation studies with an
Escherichia coli
recipient strain showed differences in the properties of the KPC variants. KPC-4 and KPC-5 both had pIs of 7.65, in contrast with the pI of 6.7 for KPC-2. KPC-2 transformants were less susceptible to the carbapenems than KPC-4 and KPC-5 transformants. These data correlated with higher rates of imipenem hydrolysis for KPC-2 than for KPC-4 and KPC-5. However, KPC-4 and KPC-5 transformants had higher ceftazidime MICs, and the enzymes from these transformants had slightly better hydrolysis of this drug than KPC-2. KPC-4 and KPC-5 were more sensitive than KPC-2 to inhibition by clavulanic acid in both susceptibility testing and hydrolysis assays. Thus, KPC enzymes may be evolving through stepwise mutations to alter their spectra of activity.
International Interlaboratory Proficiency Testing Program for Measurement of Azole Antifungal Plasma Concentrations
Authors: Brüggemann Roger J. M. , Touw Daan J. , Aarnoutse Rob E. , Verweij Paul E. , Burger David M.
Published: November 2008

An international interlaboratory proficiency testing program for the measurement of antifungal drugs was initiated in 2007. This first round was limited to azole antifungals: fluconazole, itraconazole and hydroxyitraconazole, voriconazole, and posaconazole. The results demonstrate the need for and utility of an ongoing proficiency testing program to further improve the analytical methods for routine patient management and clinical research.
Effect of a Single Dose of Ritonavir on the Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered in Healthy Volunteers
Authors: Colucci Philippe , Pottage John C. , Robison Heather , Turgeon Jacques , Ducharme Murray P.
Published: November 2008

The purpose of this study was to determine the effect of a single dose of 300 mg of ritonavir on the plasma pharmacokinetics (PK) of a single dose of 20 mg of elvucitabine when the two drugs were coadministered in healthy subjects. In a three-way crossover design, 30 subjects received 20 mg of elvucitabine, 300 mg of ritonavir, or 20 mg of elvucitabine coadministered with 300 mg of ritonavir. Elvucitabine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT-II, while a population analysis was performed using IT2S. Comparisons of PK parameters between groups were done with SAS. The pharmacokinetic behavior of elvucitabine was best described by a two-compartment linear model using two absorption rates and a first-order elimination rate. Ritonavir significantly impacted the PK of elvucitabine by reducing elvucitabine's bioavailability, with the most plausible explanation being an inhibition on influx transporters by ritonavir. The decrease in elvucitabine bioavailability when elvucitabine was coadministered with ritonavir may be due to ritonavir's inhibiting influx gut transporters. Continued development of elvucitabine is warranted to better characterize its PK and to determine its in vivo efficacy against human immunodeficiency virus.
Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults
Authors: Jacobson Jeffrey M. , Kuritzkes Daniel R. , Godofsky Eliot , DeJesus Edwin , Larson Jeffrey A. , Weinheimer Steven P. , Lewis Stanley T.
Published: November 2008

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log10) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4+T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4+T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.
Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever
Authors: Bubalo Joseph S. , Munar Myrna Y. , Cherala Ganesh , Hayes-Lattin Brandon , Maziarz Richard
Published: November 2008

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant
Staphylococcus aureus
. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (
C
max
) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to
C
max
was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved
C
max
/MIC and AUC from time zero to 24 h (AUC
0-24
)/MIC ratios for a bacteriostatic effect against
Streptococcus pneumoniae
. Twenty-seven patients (93%) achieved a
C
max
/MIC ratio for a bacteriostatic effect against
S. aureus
, and 28 patients (97%) achieved an AUC
0-24
/MIC ratio for a bacteriostatic effect against
S. aureus
. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for
S. pneumoniae
and 90% of patients for
S. aureus
. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.
Ambuic Acid Inhibits the Biosynthesis of Cyclic Peptide Quormones in Gram-Positive Bacteria
Authors: Nakayama Jiro , Uemura Yumi , Nishiguchi Kenzo , Yoshimura Norito , Igarashi Yasuhiro , Sonomoto Kenji
Published: November 2008

Quorum sensing is a cell-density-dependent regulatory system in gram-positive bacteria and is often regulated by cyclic peptides called “quormones,” which function as extracellular communication signals. With an aim to discover an antipathogenic agent targeting quorum sensing in gram-positive bacteria, we screened 153 samples of fungal butanol extracts with the guidance of the inhibition of quorum-sensing-mediated gelatinase production in
Enterococcus faecalis
. Following the screenings, we found that ambuic acid, a known secondary fungal metabolite, inhibited the quorum-sensing-mediated gelatinase production without influencing the growth of
E. faecalis.
We further demonstrated that ambuic acid targeted the biosynthesis of a cyclic peptide quormone called gelatinase biosynthesis-activating pheromone. Furthermore, ambuic acid also inhibited the biosynthesis of the cyclic peptide quormones of
Staphylococcus aureus
and
Listeria innocua.
These results suggest the potential use of ambuic acid as a lead compound of antipathogenic drugs that target the quorum-sensing-mediated virulence expression of gram-positive bacteria.
Impact of Inoculum Size and Heterogeneous Vancomycin-Intermediate
Staphylococcus aureus
(hVISA) on Vancomycin Activity and Emergence of VISA in an In Vitro Pharmacodynamic Model
Authors: Rose Warren E. , Leonard Steven N. , Rossi Kerri L. , Kaatz Glenn W. , Rybak Michael J.
Published: November 2008

The activity of vancomycin against heterogeneous vancomycin-intermediate
Staphylococcus aureus
(hVISA) and non-hVISA isolates, using an in vitro pharmacodynamic model, was reduced in the presence of a high inoculum amount (10
8
CFU/ml). A high bacterial load of >10
5
CFU/ml persisted for all strains with doses up to 5 g every 12 h against high inoculum amounts. No change in the vancomycin MIC was detected in any isolate at a moderate inoculum amount (10
6
CFU/ml), and bactericidal activity occurred only against the non-hVISA isolate (time to 99% kill, 7.5 h;
P
= 0.001).
Truncated
tni
Module Adjacent to the Complex Integron of
Salmonella
Genomic Island 1 in
Salmonella enterica
Serovar Virchow
Authors: Doublet Benoît , Chu Chishih , Chiu Cheng-Hsun , Fan Yi-Chin , Cloeckaert Axel
Published: November 2008

Salmonella
genomic island 1 was identified for the first time in
Salmonella enterica
serovar Virchow isolated from humans in Taiwan. The complex class 1 integron conferring multidrug resistance was shown to be inserted within open reading frame (ORF) S023 and contains for the first time a partial transpositional module. The 5-bp target duplication flanking the complex integron suggests that its insertion in ORF S023 was by transposition.
Activity of Levofloxacin Alone and in Combination with a DnaK Inhibitor against Gram-Negative Rods, Including Levofloxacin-Resistant Strains
Authors: Credito Kim , Lin Gengrong , Koeth Laura , Sturgess Michael A. , Appelbaum Peter C.
Published: November 2008

Synergy time-kill testing of levofloxacin alone and in combination with CHP-105, a representative DnaK inhibitor, against 50 gram-negative rods demonstrated that 34 of the 50 strains tested showed significant synergy between levofloxacin and CHP-105 after 12 h and 24 h. Fourteen of these 34 organisms were quinolone resistant (levofloxacin MICs of ≥4 μg/ml).
In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment
Authors: Soh Patrice Njomnang , Witkowski Benoît , Olagnier David , Nicolau Marie-Laure , Garcia-Alvarez Maria-Concepcion , Berry Antoine , Benoit-Vical Françoise
Published: November 2008

Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites’ resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all
Plasmodium falciparum
strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against
Plamodium vinckei petteri
in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of
Plasmodium falciparum
demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound
N
-acetyl-
l
-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on
P. falciparum
are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
In Vitro Susceptibility of Field Isolates of
Leishmania donovani
to Miltefosine and Amphotericin B: Correlation with Sodium Antimony Gluconate Susceptibility and Implications for Treatment in Areas of Endemicity
Authors: Kumar Dhiraj , Kulshrestha Arpita , Singh Ruchi , Salotra Poonam
Published: November 2008

Indian
Leishmania donovani
isolates (
n
= 19) from regional zones representing various levels of antimony resistance displayed significantly (
P
< 0.01) correlated results with respect to in vitro susceptibility to the antileishmanial drugs sodium antimony gluconate, amphotericin B, and Miltefosine, raising the possibility of cross-resistance mechanisms operating in the field isolates. The results of gene expression analysis of LdMT and LdRos3 were suggestive of alternate mechanisms of Miltefosine susceptibility in the isolates.
Activity of the Oral Neuraminidase Inhibitor A-322278 against the Oseltamivir-Resistant H274Y (A/H1N1) Influenza Virus Mutant in Mice
Authors: Baz Mariana , Abed Yacine , Nehmé Benjamin , Boivin Guy
Published: November 2008

The new oral neuraminidase (NA) inhibitor A-322278 was evaluated in mice infected with influenza A/H1N1 wild-type virus or the oseltamivir-resistant (H274Y mutant) virus. A-322278 decreased mortality rates and lung virus titers significantly more than oseltamivir in mice infected with the NA H274Y mutant when therapy was started 4 h before or even 48 h after infection.
Human Decay-Accelerating Factor and CEACAM Receptor-Mediated Internalization and Intracellular Lifestyle of Afa/Dr Diffusely Adhering
Escherichia coli
in Epithelial Cells
Authors: Guignot Julie , Hudault Sylvie , Kansau Imad , Chau Ingrid , Servin Alain L.
Published: November 2008

We used transfected epithelial CHO-B2 cells as a model to identify the mechanism mediating internalization of Afa/Dr diffusely adhering
Escherichia coli
. We provide evidence that neither the α5 or β1 integrin subunits nor α5β1 integrin functioned as a receptor mediating the adhesion and/or internalization of Dr or Afa-III fimbria-positive bacteria. We also demonstrated that (i) whether or not the AfaD or DraD invasin subunits were present, there was no difference in the cell association and entry of bacteria and that (ii) DraE or AfaE-III adhesin subunits are necessary and sufficient to promote the receptor-mediated bacterial internalization into epithelial cells expressing human decay-accelerating factor (DAF), CEACAM1, CEA, or CEACAM6. Internalization of Dr fimbria-positive
E. coli
within CHO-DAF, CHO-CEACAM1, CHO-CEA, or CHO-CEACAM6 cells occurs through a microfilament-independent, microtubule-dependent, and lipid raft-dependent mechanism. Wild-type Dr fimbria-positive bacteria survived better within cells expressing DAF than bacteria internalized within CHO-CEACAM1, CHO-CEA, or CHO-CEACAM6 cells. In DAF-positive cells, internalized Dr fimbria-positive bacteria were located in vacuoles that contained more than one bacterium, displaying some of the features of late endosomes, including the presence of Lamp-1 and Lamp-2, and some of the features of CD63 proteins, but not of cathepsin D, and were acidic. No interaction between Dr fimbria-positive-bacterium-containing vacuoles and the autophagic pathway was observed.
Immunodominance in Mouse and Human CD4+T-Cell Responses Specific for theBordetella pertussisVirulence Factor P.69 Pertactin
Authors: Stenger Rachel M. , Poelen Martien C. M. , Moret Ed E. , Kuipers Betsy , Bruijns Sven C. M. , Hoogerhout Peter , Hijnen Marcel , King Audrey J. , Mooi Frits R. , Boog Claire J. P. , van Els Cécile A. C. M.
Published: November 2008

P.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis,Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restrictedB. pertussisconserved CD4+T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination andB. pertussisinfection, and it was capable of evoking a Th1/Th17-type cytokine response.B. pertussisP.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present inBordetella parapertussisandBordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+T cells in an HLA-DQ-restricted manner. DuringB. pertussisinfection, the epitope was associated with a Th1-type CD4+T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+T-cell immunity afterB. pertussisvaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance ofB. pertussis-specific CD4+T-cell mechanisms in preclinical and clinical vaccine studies.
Localization of the Domains of the
Haemophilus ducreyi
Trimeric Autotransporter DsrA Involved in Serum Resistance and Binding to the Extracellular Matrix Proteins Fibronectin and Vitronectin
Authors: Leduc Isabelle , Olsen Bonnie , Elkins Christopher
Published: November 2008

Resisting the bactericidal activity of naturally occurring antibodies and complement of normal human serum is an important element in the evasion of innate immunity by bacteria. In the gram-negative mucosal pathogen
Haemophilus ducreyi
, serum resistance is mediated primarily by the trimeric autotransporter DsrA. DsrA also functions as an adhesin for the extracellular matrix proteins fibronectin and vitronectin and mediates attachment of
H. ducreyi
to keratinocytes. We sought to determine the domain(s) of the 236-residue DsrA protein required for serum resistance and extracellular matrix protein binding. A 140-amino-acid truncated protein containing only the C-terminal portion of the passenger domain and the entire translocator domain of DsrA exhibited binding to fibronectin and vitronectin and conferred serum resistance to an
H. ducreyi
serum-sensitive strain. A shorter DsrA construct consisting of only 128 amino acids was unable to bind to extracellular matrix proteins but was serum resistant. We concluded that neither fibronectin binding nor vitronectin binding is required for high-level serum resistance in
H. ducreyi
.
Humoral Immunity against Capsule Polysaccharide Protects the Host from
magA
+
Klebsiella pneumoniae
-Induced Lethal Disease by Evading Toll-Like Receptor 4 Signaling
Authors: Wu Ming-Fang , Yang Chih-Ya , Lin Tzu-Lung , Wang Jin-Town , Yang Feng-Ling , Wu Shih-Hsiung , Hu Bor-Shen , Chou Teh-Ying , Tsai Ming-Daw , Lin Chi-Hung , Hsieh Shie-Liang
Published: November 2008

Klebsiella pneumoniae magA
(for mucoviscosity-associated gene A) is linked to the pathogenesis of primary pyogenic liver abscess, but the underlying mechanism by which
magA
increases pathogenicity is not well elucidated. In this study, we investigated the role of the capsular polysaccharides (CPS) in the pathogenesis of
magA
+
K. pneumoniae
by comparing host immunity to
magA
+
K. pneumoniae
and a Δ
magA
mutant. We found that Toll-like receptor 4 recognition by
magA
+
K. pneumoniae
was hampered by the mucoviscosity of the
magA
+
K. pneumoniae
CPS. Interestingly, monoclonal antibodies (MAbs) against
magA
+
K. pneumoniae
CPS recognized all of the K1 strains tested but not the Δ
magA
and non-K1 strains. Moreover, the anti-CPS MAbs protected mice from
magA
+
K. pneumoniae
-induced liver abscess formation and lethality. This indicates that the K1 epitope is a promising target for vaccine development, and anti-CPS MAbs has great potential to protect host from K1 strain-induced mortality and morbidity in diabetic and other immunocompromised patients in the future.
Immune Response and Alveolar Bone Resorption in a Mouse Model ofTreponema denticolaInfection
Authors: Lee Song F. , Andrian Elisoa , Rowland Elden , Marquez Ignacio Christian
Published: November 2008

Treponema denticolais considered to be an agent strongly associated with periodontal disease. The lack of an animal infection model has hampered the understanding ofT. denticolapathogenesis and the host's immune response to infection. In this study, we have established an oral infection model in mice, demonstrating that infection by oral inoculation is feasible. The presence ofT. denticolain the oral cavities of the animals was confirmed by PCR. Mice givenT. denticoladeveloped a specific immune response to the bacterium. The antibodies generated from the infection were mainly of the immunoglobulin G1 subclass, indicating a Th2-tilted response. The antibodies recognized 11T. denticolaproteins, of which a 62-kDa and a 53-kDa protein were deemed immunodominant. The two proteins were identified, respectively, as dentilisin and the major outer sheath protein by mass spectrometry. Splenocytes cultured from the infected mice no longer produced interleukin-10 and produced markedly reduced levels of gamma interferon relative to those produced by naïve splenocytes upon stimulation withT. denticola. Mandibles of infected mice showed significantly greater bone resorption (P< 0.01) than those of mock-infected controls.
Effect ofPlasmodium yoeliiExposure on Vaccination with the 19-Kilodalton Carboxyl Terminus of Merozoite Surface Protein 1 and Vice Versa and Implications for the Application of a Human Malaria Vaccine
Authors: Wipasa Jiraprapa , Xu Huji , Liu Xueqin , Hirunpetcharat Chakrit , Stowers Anthony , Good Michael F.
Published: November 2008

It is well known that exposure to one antigen can modulate the immune responses that develop following exposure to closely related antigens. It is also known that the composition of the repertoire can be skewed to favor epitopes shared between a current infection and a preceding one, a phenomenon referred to as “original antigenic sin.” It was of interest, therefore, to investigate the antibody response that develops following exposure to the malaria vaccine candidate homologuePlasmodium yoeliiMSP119in mice that had previously experienced malaria infection and vice versa. In this study, preexposure of mice toPlasmodium yoeliielicited native anti-MSP119antibody responses, which could be boosted by vaccination with recombinant MSP119. Likewise, infection of MSP119-primed mice withP. yoeliiled to an increase of anti-MSP119antibodies. However, this increase was at the expense of antibodies to parasite determinants other than MSP119. This change in the balance of antibody specificities significantly affected the ability of mice to withstand a subsequent infection. These data have particular relevance to the possible outcome of malaria vaccination for those situations where the vaccine response is suboptimal and suggest that suboptimal vaccination may in fact render the ultimate acquisition of natural immunity more difficult.
Interleukin-15 and NK1.1+Cells Provide Innate Protection against AcuteSalmonella entericaSerovar Typhimurium Infection in the Gut and in Systemic Tissues
Authors: Ashkar Ali A. , Reid Sarah , Verdu Elena F. , Zhang Kun , Coombes Brian K.
Published: November 2008

Control of bacterial colonization at mucosal surfaces depends on rapid activation of the innate immune system. Interleukin-15 (IL-15) directs the development, maturation, and function of a population of cells positive for NK1.1, such as natural killer (NK) cells, which are critical components of the innate immune defense against several viral and bacterial pathogens. Using IL-15-deficient mice, in vivo depletion of NK1.1+cells from wild-type mice, and in vivo overexpression of IL-15 from a recombinant adenovirus, we tested the role of IL-15 and NK1.1+cells in innate protection of the murine gut and reticuloendothelial system fromSalmonella entericaserovar Typhimurium infection. IL-15 and the NK1.1+cell population provided innate protection from serovar Typhimurium in mice at the enteric mucosae and in the reticuloendothelial system during murine typhoid. Interestingly, serovar Typhimurium extensively colonized the gut of IL-15−/−mice and wild-type C57BL/6 mice depleted of NK1.1+cells prior to infection, even though the animals were not pretreated with antibiotics to reduce colonization resistance and there was an absence of overt inflammation in the colon and cecum. Enhanced dissemination ofSalmonellafrom the gut of mice depleted of NK1.1+cells correlated with a localized disruption of IL-17 in the colon. These data suggest a relationship between the gut ecosystem and the innate mucosal immune system, which may be linked via IL-15 and NK1.1+cells.