bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiative Properties of Semitransparent Silicon Wafers With Rough Surfaces
Authors: Zhou Y. H. , Zhang Z. M.
Published: May 2003

This paper presents a Monte Carlo model for prediction of the radiative properties of semitransparent silicon wafers with rough surfaces. This research was motivated by the need of accurate temperature measurement in rapid thermal processing (RTP) systems. The methods developed in this paper, however, can be applied to various semitransparent materials, such as diamond films. The numerically obtained bidirectional reflectance distribution function (BRDF) showed a similar trend as the experimental data. Furthermore, a higher angular resolution can be achieved by simulation than by experiments. The bidirectional transmittance distribution function (BTDF) can also be computed in the same run for semitransparent wafers. Other spectral radiative properties (such as the directional-hemispherical transmittance and reflectance, the emittance and the absorptance) under various surface conditions were computed at various temperatures. The results can help gain a deeper understanding of the radiative behavior of semitransparent materials and may be applied to various fields.
Heat Transfer Enhancement Caused by Sliding Bubbles
Authors: Bayazit Baris B. , Hollingsworth D. Keith , Witte Larry C.
Published: May 2003

Measurements that illustrate the enhancement of heat transfer caused by a bubble sliding under an inclined surface are reported. The data were obtained on an electrically heated thin-foil surface that was exposed on its lower side to FC-87 and displayed the output of a liquid crystal coating on the upper (dry) side. A sequence of digital images was obtained from two cameras: one that recorded the response of the liquid crystal and one that recorded images of the bubble as it moved along the heated surface. With this information, the thermal imprint of the bubble was correlated to its motion and position. A bubble generator that produced FC-87 bubbles of repeatable and controllable size was also developed for this study. The results show that both the microlayer under a sliding bubble and the wake behind the bubble contribute substantially to the local heat transfer rate from the surface. The dynamic behavior of the bubbles corresponded well with studies of the motion of adiabatic bubbles under inclined plates, even though the bubbles in the present study grew rapidly because of heat transfer from the wall and the surrounding superheated liquid. Three regimes of bubble motion were observed: spherical, ellipsoidal and bubble-cap. The regimes depend upon bubble size and velocity. A model of the heat transfer within the microlayer was used to infer the microlayer thickness. Preliminary results indicate a microlayer thickness of 40–50 μm for bubbles in FC-87 and a plate inclination of 12 deg.
Nodal Integral and Finite Difference Solution of One-Dimensional Stefan Problem
Authors: Caldwell James , Savovic´ Svetislav , Kwan Yuen-Yick
Published: May 2003

The nodal integral and finite difference methods are useful in the solution of one-dimensional Stefan problems describing the melting process. However, very few explicit analytical solutions are available in the literature for such problems, particularly with time-dependent boundary conditions. Benchmark cases are presented involving two test examples with the aim of producing very high accuracy when validated against the exact solutions. Test example 1 (time-independent boundary conditions) is followed by the more difficult test example 2 (time-dependent boundary conditions). As a result, the temperature distribution, position of the moving boundary and the velocity are evaluated and the results are validated.
A MEMS Piston-Cylinder Device Actuated by Combustion
Authors: Lee Dae Hoon , Park Dae-Eun , Yoon Euisik , Kwon Sejin
Published: May 2003

Combustion measurement in a cylindrical micro combustor, the construction procedure and test run of a MEMS reciprocating device are described. The sizing of the MEMS device was based on the findings of combustion measurements. Thermodynamic analysis of the pressure measurement resulted in available work up to 2.4 Joules in a combustor height of 2 mm and more with combustion efficiency of 0.6∼0.7. With combustor height less than 2 mm, combustion was incomplete due to excessive heat loss to the wall. In order to achieve the chamber height imposed by the combustion measurement, a fabrication process and wafer material that allow deeper etching was used.
Heat Transfer Coefficients and Film-Cooling Effectiveness on a Gas Turbine Blade Tip
Authors: Kwak Jae Su , Han Je-Chin
Published: May 2003

The detailed distributions of heat transfer coefficient and film cooling effectiveness on a gas turbine blade tip were measured using a hue detection based transient liquid crystals technique. Tests were performed on a five-bladed linear cascade with blow-down facility. The Reynolds number based on cascade exit velocity and axial chord length was 1.1×106 and the total turning angle of the blade was 97.7°. The overall pressure ratio was 1.2 and the inlet and exit Mach numbers were 0.25 and 0.59, respectively. The turbulence intensity level at the cascade inlet was 9.7%. The blade model was equipped with a single row of film cooling holes at both the tip portion along the camber line and near the tip region of the pressure side. All measurements were made at the three different tip gap clearances of 1.0%, 1.5%, and 2.5% of blade span and the three blowing ratios of 0.5, 1, and 2. Results showed that, in general, heat transfer coefficient and film effectiveness increased with increasing tip gap clearance. As blowing ratio increased, heat transfer coefficient decreased, while film effectiveness increased. Results also showed that adding pressure side coolant injection would further decrease the blade tip heat transfer coefficient but increase film-cooling effectiveness.
A General Expression for the Determination of the Log Mean Temperature Correction Factor for Shell and Tube Heat Exchangers
Authors: Fakheri Ahmad
Published: May 2003

This paper presents a single closed form algebraic equation for the determination of the Log Mean Temperature Difference correction factor F for shell and tube heat exchangers having N shell passes and 2M tube passes per shell. The equation and its graphical presentation generalize the traditional equations and charts used for the determination of F. The equation presented is also useful in design, analysis and optimization of multi shell and tube heat exchanger, particularly for direct determination of the number of shells.
Duality of Heat Exchanger Performance in Balanced Counter-Flow Systems
Authors: Ogiso Ken
Published: May 2003

The duality of heat exchangers to act as both heat conductors and insulators when considering heat exchanger performance is studied from the viewpoint of entropy generation. By defining an appropriate index of the entropy generation rate, it is clarified that the performance paradox pointed out by Bejan can be resolved. The case of a balanced counter-flow system was examined and it has been shown that a heat exchanger can be regarded as both a heat conductor and a heat insulator in terms of entropy generation.
Thermal Resistance for Random Contacts on the Surface of a Semi-Infinite Heat Flux Tube
Authors: Laraqi N.
Published: May 2003

Analytical solution is developed to calculate the thermal constriction resistance for contacts randomly distributed on the surface of a laterally insulated semi-infinite square prism. The contacts are modeled by circular spots with different radii and uniform heat flux. We analyze the evolution of the thermal constriction resistance as a function of the number of contacts, the relative contact size, and the dispersion of radii of spots. We show that the thermal constriction resistance for random contacts is a few tens of percents greater than that of the regular contacts.
Simulation of Compressible Micro-Scale Jet Impingement Heat Transfer
Authors: Pence Deborah V. , Boeschoten Paul A. , Liburdy James A.
Published: May 2003

A computational study is presented of the heat transfer performance of a micro-scale, axisymmetric, confined jet impinging on a flat surface with an embedded uniform heat flux disk. The jet flow occurs at large, subsonic Mach numbers (0.2 to 0.8) and low Reynolds numbers (419 to 1782) at two impingement distances. The flow is characterized by a Knudsen number of 0.01, based on the viscous boundary layer thickness, which is large enough to warrant consideration of slip-flow boundary conditions along the impingement surface. The effects of Mach number, compressibility, and slip-flow on heat transfer are presented. The local Nusselt number distributions are shown along with the velocity, pressure, density and temperature fields near the impingement surface. Results show that the wall temperature decreases with increasing Mach number, M, exhibiting a minimum local value at r/R=1.6 for the highest M. The slip velocity also increases with M, showing peak values near r/R=1.4 for all M. The resulting Nusselt number increases with increasing M, and local maxima are observed near r/R=1.20, rather than at the centerline. In general, compressibility improves heat transfer due to increased fluid density near the impinging surface. The inclusion of slip-velocity and the accompanying wall temperature jump increases the predicted rate of heat transfer by as much as 8–10% for M between 0.4 and 0.8.
A Parabolic Temperature Profile Model for Heating of Droplets
Authors: Dombrovsky L. A. , Sazhin S. S.
Published: May 2003

A model for convective heating of droplets, which takes into account their finite thermal conductivity, is suggested. This model is based on the assumption of the parabolic temperature profile in the droplets. A rigorous numerical solution, without restrictions on temperature profiles inside droplets, is compared with predictions of the parabolic temperature profile and isothermal models. The comparison shows the applicability of the parabolic approximation to modelling of the heating of fuel droplets in realistic diesel engines. The simplicity of the model makes it particularly convenient for implementation into CFD codes.
Temperature Measurements Using a High-Temperature Blackbody Optical Fiber Thermometer
Authors: Barker David G. , Jones Matthew R.
Published: May 2003

A blackbody optical fiber thermometer consists of an optical fiber whose sensing tip is given a metallic coating. The sensing tip of the fiber forms an isothermal cavity and the emission from this cavity is approximately equal to the emission from a blackbody. When a short length of the fiber is exposed to a high temperature environment, the temperature at the sensing tip can be inferred using the standard two-color approach. If, however, more than a short length of the fiber is exposed to elevated temperatures, emission by the fiber will result in erroneous temperature measurements. This paper presents experimental results that show it is possible to use additional spectral measurements to eliminate errors due to emission by the fiber and measure the tip temperature. In addition, the technique described in this paper can be used to obtain an estimate of the temperature profile along the fiber.
Numerical Prediction of Flow and Heat Transfer in a Rectangular Channel With a Built-In Circular Tube
Authors: Tiwari S. , Biswas G. , Prasad P. L. N. , Basu Sudipta
Published: May 2003

A numerical investigation of flow and heat transfer in a rectangular duct with a built-in circular tube was carried out for moderate Reynolds numbers and varying blockage ratios. Since the heat transfer in the duct is dictated by the flow structure, the study was directed towards characterization of the flow. To this end, the topological theory shows promise of becoming a powerful tool for the study of flow structures. The limiting streamlines on the tube and the bottom plate reveal a complex flow field. The separation lines and points of singularity (saddle points and nodal points) were investigated. The iso-Nusselt number contours and span-averaged Nusselt number distribution in the flow passage shed light on the heat transfer performance in the duct. The investigation was necessitated by the need to enhance heat transfer in fin-tube heat exchangers through identification of the zones of poor heat transfer. The predicted results compare well with the well documented experimental results available in the literature. In the range of Reynolds numbers considered for the present case, no need is felt to employ any turbulence model in order to describe the heat transfer behavior. Time series signals of the transverse velocity component in the wake zone are presented with their FFT and time-delay plots. The onset of turbulence is not observed up to the highest value of the Reynolds number considered in the present case. This confirms that the transition to turbulence is delayed in the present case compared with that observed for flow past a circular tube placed in an infinite medium. The reason may be attributed to the narrow gap between the no-slip channel walls.
Keeping G Proteins at Bay: A Complex Between G Protein-Coupled Receptor Kinase 2 and Gßγ
Authors: Lodowski David T. , Pitcher Julie A. , Capel W. Darrell , Lefkowitz Robert J. , Tesmer John J. G.
Published: May 2003

The phosphorylation of heptahelical receptors by heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor kinases (GRKs) is a universal regulatory mechanism that leads to desensitization of G protein signaling and to the activation of alternative signaling pathways.We determined the crystallographic structure of bovine GRK2 in complex with G protein β
1
γ
2
subunits.Our results show how the three domains of GRK2–the RGS (regulator of G protein signaling) homology, protein kinase, and pleckstrin homology domains–integrate their respective activities and recruit the enzyme to the cell membrane in an orientation that not only facilitates receptor phosphorylation, but also allows for the simultaneous inhibition of signaling by Gα and Gβγ subunits.
The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in
Alu
Exons
Authors: Lev-Maor Galit , Sorek Rotem , Shomron Noam , Ast Gil
Published: May 2003

Alu
repetitive elements can be inserted into mature messenger RNAs via a splicing-mediated process termed exonization. To understand the molecular basis and the regulation of the process of turning intronic
Alu
s into new exons, we compiled and analyzed a data set of human exonized
Alu
s. We revealed a mechanism that governs 3′ splice-site selection in these exons during alternative splicing. On the basis of these findings, we identified mutations that activated the exonization of a silent intronic
Alu
.
Orbital Motion in the Radio Galaxy 3C 66B: Evidence for a Supermassive Black Hole Binary
Authors: Sudou Hiroshi , Iguchi Satoru , Murata Yasuhiro , Taniguchi Yoshiaki
Published: May 2003

Supermassive black hole binaries may exist in the centers of active galactic nuclei such as quasars and radio galaxies, and mergers between galaxies may result in the formation of supermassive binaries during the course of galactic evolution. Using the very-long-baseline interferometer, we imaged the radio galaxy 3C 66B at radio frequencies and found that the unresolved radio core of 3C 66B shows well-defined elliptical motions with a period of 1.05 ± 0.03 years, which provides a direct detection of a supermassive black hole binary.
Essential Role of Fkbp6 in Male Fertility and Homologous Chromosome Pairing in Meiosis
Authors: Crackower Michael A. , Kolas Nadine K. , Noguchi Junko , Sarao Renu , Kikuchi Kazuhiro , Kaneko Hiroyuki , Kobayashi Eiji , Kawai Yasuhiro , Kozieradzki Ivona , Landers Rushin , Mo Rong , Hui Chi-Chung , Nieves Edward , Cohen Paula E. , Osborne Lucy R. , Wada Teiji , Kunieda Tetsuo , Moens Peter B. , Penninger Josef M.
Published: May 2003

Meiosis is a critical stage of gametogenesis in which alignment and synapsis of chromosomal pairs occur, allowing for the recombination of maternal and paternal genomes. Here we show that FK506 binding protein (Fkbp6) localizes to meiotic chromosome cores and regions of homologous chromosome synapsis. Targeted inactivation of
Fkbp6
in mice results in aspermic males and the absence of normal pachytene spermatocytes. Moreover, we identified the deletion of
Fkbp6
exon 8 as the causative mutation in spontaneously male sterile
as
/
as
mutant rats. Loss of Fkbp6 results in abnormal pairing and misalignments between homologous chromosomes, nonhomologous partner switches, and autosynapsis of X chromosome cores in meiotic spermatocytes. Fertility and meiosis are normal in
Fkbp6
mutant females. Thus, Fkbp6 is a component of the synaptonemal complex essential for sex-specific fertility and for the fidelity of homologous chromosome pairing in meiosis.
Ferroelectricity in Free Niobium Clusters
Authors: Moro Ramiro , Xu Xiaoshan , Yin Shuangye , de Heer Walt A.
Published: May 2003

Electric deflections of gas-phase, cryogenically cooled, neutral niobium clusters [Nb

N

; number of atoms (
N
) = 2 to 150, temperature (
T
) = 20to 300kelvin], measured in molecular beams, show that cold clusters may attain an anomalous component with very large electric dipole moments. In contrast, room-temperature measurements show normal metallic polarizabilities. Characteristic energies
k
B
T
G
(
N
) [Boltzmann constant
k
B
times a transition temperature
T
G
(
N
)] are identified, below which the ferroelectric-like state develops. Generally,
T
G
decreases [110 >
T
G
(
N
) > 10K] as
N
increases, with pronounced even-odd alternations for
N
> 38. This new state of metallic matter may be related to bulk superconductivity.
Europe's Terrestrial Biosphere Absorbs 7 to 12% of European Anthropogenic CO
2
Emissions
Authors: Janssens Ivan A. , Freibauer Annette , Ciais Philippe , Smith Pete , Nabuurs Gert-Jan , Folberth Gerd , Schlamadinger Bernhard , Hutjes Ronald W. A. , Ceulemans Reinhart , Schulze E.-Detlef , Valentini Riccardo , Dolman A. Johannes
Published: May 2003

Most inverse atmospheric models report considerable uptake of carbon dioxide in Europe's terrestrial biosphere. In contrast, carbon stocks in terrestrial ecosystems increase at a much smaller rate, with carbon gains in forests and grassland soils almost being offset by carbon losses from cropland and peat soils. Accounting for non–carbon dioxide carbon transfers that are not detected by the atmospheric models and for carbon dioxide fluxes bypassing the ecosystem carbon stocks considerably reduces the gap between the small carbon-stock changes and the larger carbon dioxide uptake estimated by atmospheric models. The remaining difference could be because of missing components in the stock-change approach, as well as the large uncertainty in both methods. With the use of the corrected atmosphere- and land-based estimates as a dual constraint, we estimate a net carbon sink between 135 and 205 teragrams per year in Europe's terrestrial biosphere, the equivalent of 7 to 12% of the 1995 anthropogenic carbon emissions.
Deformation Twinning in Nanocrystalline Aluminum
Authors: Chen Mingwei , Ma En , Hemker Kevin J. , Sheng Hongwei , Wang Yinmin , Cheng Xuemei
Published: May 2003

We report transmission electron microscope observations that provide evidence of deformation twinning in plastically deformed nanocrystalline aluminum. The presence of these twins is directly related to the nanocrystalline structure, because they are not observed in coarse-grained pure aluminum. We propose a dislocation-based model to explain the preference for deformation twins and stacking faults in nanocrystalline materials. These results underscore a transition from deformation mechanisms controlled by normal slip to those controlled by partial dislocation activity when grain size decreases to tens of nanometers, and they have implications for interpreting the unusual mechanical behavior of nanocrystalline materials.
Geometric Origin of Hexagonal Close Packing at a Grain Boundary in Gold
Authors: Lucadamo G. , Medlin D. L.
Published: May 2003

Using electron microscopy, we identify local, intergranular regions of hexagonal close-packing at a grain boundary in gold. By analyzing the topological defects that connect this layer to the adjacent face-centered cubic grains, we explain the geometric origin of this interfacial reconstruction. We extend this analysis to predict the stacking arrangements found over a range of intergranular misorientations. These results help to unify our understanding of the defects that control the behavior of polycrystalline materials by showing how line defects that are already well understood in the bulk also can determine the atomic arrangements at grain boundaries.
Recruitment of HIV and Its Receptors to Dendritic Cell-T Cell Junctions
Authors: McDonald David , Wu Li , Bohks Stacy M. , KewalRamani Vineet N. , Unutmaz Derya , Hope Thomas J.
Published: May 2003

Monocyte-derived dendritic cells (MDDCs) can efficiently bind and transfer HIV infectivity without themselves becoming infected. Using live-cell microscopy, we found that HIV was recruited to sites of cell contact in MDDCs. Analysis of conjugates between MDDCs and T cells revealed that, in the absence of antigen-specific signaling, the HIV receptors CD4, CCR5, and CXCR4 on the T cell were recruited to the interface while the MDDCs concentrated HIV to the same region. We propose that contact between dendritic cells and T cells facilitates transmission of HIV by locally concentrating virus, receptor, and coreceptor during the formation of an infectious synapse.
So Many People, So Little Water
Authors: Henderson A. Scott
Published: May 2003

Fuel for Growth
Water and Arizona's Urban Environment. Douglas E. Kupel. University of Arizona Press, Tucson, 2003. 319 pp. $39.95. ISBN 0-8165-2169-7.

Examining the interplay between urban development and water development in Arizona, Kupel argues that the culture that settlers brought with them from the humid Midwest and East proved more important than aridity, environmental sustainability, and differences in ecological settings.
Equality of the Sexes
Authors: Godfray H. C. J.
Published: May 2003

Sex Ratios
Concepts and Research Methods. Ian C. W. Hardy, Ed. Cambridge University Press, Cambridge, 2002. 438 pp. $120, £90. ISBN 0-521-81896-6. Paper, $48, £32.95. ISBN 0-521-66578-7.

Covering such topics as sex allocation, sex determination, and operational sex ra-tios, the contributors offer evolutionary biologists a conceptual and methodological background for sex-ratio research.
Illuminating the Circadian Clock in Monarch Butterfly Migration
Authors: Froy Oren , Gotter Anthony L. , Casselman Amy L. , Reppert Steven M.
Published: May 2003

Migratory monarch butterflies use a time-compensated Sun compass to navigate to their overwintering grounds in Mexico. Here, we report that constant light, which disrupts circadian clock function at both the behavioral and molecular levels in monarchs, also disrupts the time-compensated component of flight navigation. We further show that ultraviolet light is important for flight navigation but is not required for photic entrainment of circadian rhythms. Tracing these distinct light-input pathways into the brain should aid our understanding of the clock-compass mechanisms necessary for successful migration.
Atomic Memory for Correlated Photon States
Authors: van der Wal C. H. , Eisaman M. D. , André A. , Walsworth R. L. , Phillips D. F. , Zibrov A. S. , Lukin M. D.
Published: May 2003

We experimentally demonstrate emission of two quantum-mechanically correlated light pulses with a time delay that is coherently controlled via temporal storage of photonic states in an ensemble of rubidium atoms. The experiment is based on Raman scattering, which produces correlated pairs of spin-flipped atoms and photons, followed by coherent conversion of the atomic states into a different photon beam after a controllable delay. This resonant nonlinear optical process is a promising technique for potential applications in quantum communication.
Macrolide Resistance by Ribosomal Mutation in Clinical Isolates of
Streptococcus pneumoniae
from the PROTEKT 1999-2000 Study
Authors: Farrell D. J. , Douthwaite S. , Morrissey I. , Bakker S. , Poehlsgaard J. , Jakobsen L. , Felmingham D.
Published: May 2003

Sixteen (1.5%) of the 1,043 clinical macrolide-resistant
Streptococcus pneumoniae
isolates collected and analyzed in the 1999-2000 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) study have resistance mechanisms other than rRNA methylation or efflux. We have determined the macrolide resistance mechanisms in all 16 isolates by sequencing the L4 and L22 riboprotein genes, plus relevant segments of the four genes for 23S rRNA, and the expression of mutant rRNAs was analyzed by primer extension. Isolates from Canada (
n
= 4), Japan (
n
= 3), and Australia (
n
= 1) were found to have an A2059G mutation in all four 23S rRNA alleles. The Japanese isolates additionally had a G95D mutation in riboprotein L22; all of these originated from the same collection center and were clonal. Three of the Canadian isolates were also clonal; the rest were not genetically related. Four German isolates had A2059G in one, two, and three 23S rRNA alleles and A2058G in two 23S rRNA alleles, respectively. An isolate from the United States had C2611G in three 23S rRNA alleles, one isolate from Poland had A2058G in three 23S rRNA alleles, one isolate from Turkey had A2058G in four 23S rRNA alleles, and one isolate from Canada had A2059G in two 23S rRNA alleles. Erythromycin and clindamycin resistance gradually increased with the number of A2059G alleles, whereas going from one to two mutant alleles caused sharp rises in the azithromycin, roxithromycin, and rokitamycin MICs. Comparisons of mutation dosage with rRNA expression indicates that not all alleles are equally expressed. Despite their high levels of macrolide resistance, all 16 isolates remained susceptible to the ketolide telithromycin (MICs, 0.015 to 0.25 μg/ml).
Variable Sensitivity to Bacterial Methionyl-tRNA Synthetase Inhibitors Reveals Subpopulations of
Streptococcus pneumoniae
with Two Distinct Methionyl-tRNA Synthetase Genes
Authors: Gentry Daniel R. , Ingraham Karen A. , Stanhope Michael J. , Rittenhouse Stephen , Jarvest Richard L. , O'Hanlon Peter J. , Brown James R. , Holmes David J.
Published: May 2003

As reported previously (J. R. Jarvest et al., J. Med. Chem. 45:1952-1962, 2002), potent inhibitors (at nanomolar concentrations) of
Staphylococcus aureus
methionyl-tRNA synthetase (MetS; encoded by
metS1
) have been derived from a high-throughput screening assay hit. Optimized compounds showed excellent activities against staphylococcal and enterococcal pathogens. We report on the bimodal susceptibilities of
S. pneumoniae
strains, a significant fraction of which was found to be resistant (MIC, ≥8 mg/liter) to these inhibitors. Using molecular genetic techniques, we have found that the mechanism of resistance is the presence of a second, distantly related MetS enzyme, MetS2, encoded by
metS2
. We present evidence that the
metS2
gene is necessary and sufficient for resistance to MetS inhibitors. PCR analysis for the presence of
metS2
among a large sample (
n
= 315) of
S. pneumoniae
isolates revealed that it is widespread geographically and chronologically, occurring at a frequency of about 46%. All isolates tested also contained the
metS1
gene. Searches of public sequence databases revealed that
S. pneumoniae
MetS2 was most similar to MetS in
Bacillus anthracis
, followed by MetS in various non-gram-positive bacterial, archaeal, and eukaryotic species, with streptococcal MetS being considerably less similar. We propose that the presence of
metS2
in specific strains of
S. pneumoniae
is the result of horizontal gene transfer which has been driven by selection for resistance to some unknown class of naturally occurring antibiotics with similarities to recently reported synthetic MetS inhibitors.
Susceptibilities to Levofloxacin in
Streptococcus pneumoniae
,
Haemophilus influenzae
, and
Moraxella catarrhalis
Clinical Isolates from Children: Results from 2000-2001 and 2001-2002 TRUST Studies in the United States
Authors: Karlowsky James A. , Thornsberry Clyde , Critchley Ian A. , Jones Mark E. , Evangelista Alan T. , Noel Gary J. , Sahm Daniel F.
Published: May 2003

Among respiratory tract isolates of
Streptococcus pneumoniae
from children, resistance to penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole (SXT) increases on an annual basis. Pediatric patients who do not respond to conventional therapy for respiratory tract infections someday may be treated with fluoroquinolones. In this study, MICs of β-lactams, azithromycin, SXT, and levofloxacin were determined and interpreted by using NCCLS guidelines for isolates of
S. pneumoniae
(2,834 from children and 10,966 from adults),
Haemophilus influenzae
(629 from children and 2,281 from adults), and
Moraxella catarrhalis
(389 from children and 1,357 from adults) collected during the 2000-2001 and 2001-2002 respiratory illness seasons in the United States as part of the ongoing TRUST surveillance studies. Rates of resistance to penicillin, azithromycin, and SXT were ≥7.5% higher among patients ≤4 years old than among patients 5 to 10, 11 to 17, and ≥18 years old in both the 2000-2001 and the 2001-2002 respiratory illness seasons. Levofloxacin resistance was detected in 2 of 2,834 isolates (0.07%) from patients <18 years old. Levofloxacin MICs of 0.25 to 1 μg/ml accounted for 99.6, 99.5, 99.3, 99.7, 98.4, and 98.0% of isolates from patients <2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and >64 years old. Multidrug resistance was twice as common among patients ≤4 years old (25.3%) as among patients 5 to 10 years old (13.7%), 11 to 17 years old (11.9%), 18 to 64 years old (12.1%), and >64 years old (12.4%). The most common multidrug resistance phenotype in
S. pneumoniae
isolates for all age groups was resistance to penicillin, azithromycin, and SXT (70.3 to 76.6%). For
H. influenzae
and
M. catarrhalis
isolates from patients <2, 2 to 4, 5 to 10, 11 to 17, 18 to 64, and >64 years old, levofloxacin MICs at which 90% of the isolates were inhibited were 0.015 and 0.03 to 0.06 μg/ml, respectively, in the 2000-2001 and 2001-2002 respiratory illness seasons. In the 2000-2001 and 2001-2002 respiratory illness season surveillance studies in the United States, 99.9% of pediatric isolates of
S. pneumoniae
were susceptible to levofloxacin. If fluoroquinolones become a treatment option for pediatric patients, careful monitoring of fluoroquinolone susceptibilities will be increasingly important in future surveillance studies.
Oral Bioavailability and In Vivo Efficacy of the Helicase-Primase Inhibitor BILS 45 BS against Acyclovir-Resistant Herpes Simplex Virus Type 1
Authors: Duan Jianmin , Liuzzi Michel , Paris William , Liard Francine , Browne Abigail , Dansereau Nathalie , Simoneau Bruno , Faucher Anne-Marie , Cordingley Michael G.
Published: May 2003

This study investigated the oral bioavailability and efficacy of BILS 45 BS, a selective herpes simplex virus (HSV) helicase-primase inhibitor, against acyclovir (ACV)-resistant (ACV
r
) infections mediated by the HSV type 1 (HSV-1)
dl
sptk and PAA
r
5 mutant strains. In vitro, the compound was more potent than ACV against wild-type clinical and laboratory HSV-1 strains and ACV
r
HSV isolates, as determined by a standard plaque reduction assay, with a mean 50% effective concentration of about 0.15 μM. The oral bioavailability of BILS 45 BS in hairless mice was 49%, with a peak concentration in plasma of 31.5 μM after administration of a single dose of 25 mg/kg. Following cutaneous infection of nude mice, both the HSV-1
dl
sptk and PAA
r
5 mutant strains induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. Oral treatment with ACV (100 or 125 mg/kg/day, three times a day by gavage) did not affect either mutant-induced infection. In contrast, BILS 45 BS at an oral dose of 100 mg/kg/day almost completely abolished cutaneous lesions mediated by both ACV
r
HSV-1 mutants. The 50% effective doses of BILS 45 BS were 56.7 and 61 mg/kg/day against
dl
sptk- and PAA
r
5-induced infections, respectively. Taken together, our results demonstrate very effective oral therapy of experimental ACV
r
HSV-1 infections in nude mice and support the potential use of HSV helicase-primase inhibitors for the treatment of nucleoside-resistant HSV disease in humans.
Ciclopirox Olamine Treatment Affects the Expression Pattern ofCandida albicansGenes Encoding Virulence Factors, Iron Metabolism Proteins, and Drug Resistance Factors
Authors: Niewerth Markus , Kunze Donika , Seibold Michael , Schaller Martin , Korting Hans Christian , Hube Bernhard
Published: May 2003

The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47Candida albicansgenes in cells grown in the presence of a subinhibitory concentration (0.6 μg/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such asACT1was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1,FTR2,FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl3to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1,FTR2). While serum-induced yeast-to-hyphal phase transition ofC. albicanswas not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although theCandidadrug resistance genesCDR1andCDR2were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms causedC. albicansresistance to this drug even after long-term exposure.
Voriconazole Inhibits Fungal Growth without Impairing Antigen Presentation or T-Cell Activation
Authors: Van Epps Heather L. , Feldmesser Marta , Pamer Eric G.
Published: May 2003

Invasive aspergillosis (IA) is the most common life-threatening invasive mold infection worldwide. The principal therapy for IA is amphotericin B, despite its known toxicity and immunosuppressive side effects. Studies in animal models of IA suggest a role for T lymphocytes in the pathology of the disease, although the precise role forAspergillus-specific T cells remains undefined. The isolation and characterization of T lymphocytes in animal models of IA are hampered by the rapid outgrowth of the fungus in cultures derived from infected organs. In the present study, we tested the abilities of the antifungal drugs caspofungin acetate and voriconazole to inhibit fungal growth in vitro as a means of maintaining cultures of T cells fromAspergillus-infected mice. We demonstrate that while both antifungal drugs are inhibitory, only voriconazole completely inhibited fungal growth, allowing long-term maintenance of T-cell cultures. In addition, voriconazole had no inhibitory effect on the activation and maturation of dendritic cells or the proliferation of T lymphocytes. Thus, voriconazole appears to be a promising agent for use in in vitro studies ofAspergillus-specific T lymphocytes in animal models of IA.
Worldwide Assessment of Linezolid's Clinical Safety and Tolerability: Comparator-Controlled Phase III Studies
Authors: Rubinstein Ethan , Isturiz Raul , Standiford Harold C. , Smith Leon G. , Oliphant Thomas H. , Cammarata Sue , Hafkin Barry , Le Vu , Remington Jack
Published: May 2003

Linezolid, an oxazolidinone antibiotic, has 100% oral bioavailability and favorable activities against gram-positive pathogens including multidrug-resistant staphylococci, enterococci, and pneumococci. Safety assessments were conducted for 2,046 linezolid-treated patients and 2,001 comparator drug-treated patients from seven controlled clinical trials comparing the activities of linezolid and comparator drugs against nosocomial and community-acquired pneumonia, skin and skin structure infections, and methicillin-resistant staphylococcal infections. Drug-related adverse events were primarily transient. The most frequent (≥2%) adverse events caused by linezolid and the comparator drugs were diarrhea (4.3 and 3.2%, respectively;P= 0.074), nausea (3.4 and 2.3%, respectively;P= 0.036), and headache (2.2 and 1.3%, respectively;P= 0.047). Treatment discontinuations due to drug-related events (2.4 and 1.9%, respectively), serious adverse events (11.4 and 10.6%, respectively), and deaths (4.8 and 4.9%, respectively) were similar. No clinically significant drug-related hematologic events were reported, and laboratory safety data were comparable. In the first 6 months of postmarketing surveillance, hematologic abnormalities were reported in 0.1% of linezolid-treated patients, but no irreversible blood dyscrasias were documented. The risk for transient, reversible hematologic effects from treatment with linezolid should be considered together with the clinical benefits associated with its use.
Antimicrobial Resistance of Invasive Pneumococci in Finland in 1999-2000
Authors: Pihlajamäki Marja , Jalava Jari , Huovinen Pentti , Kotilainen Pirkko
Published: May 2003

The resistance patterns and macrolide resistance mechanisms of 910 Finnish invasive pneumococci isolated during 1999 and 2000 were studied. Macrolide resistance was detected in 6.9% of isolates. Penicillin resistance was detected in 1.5% of isolates, and penicillin intermediate resistance was detected in 4.0% of isolates. Active macrolide efflux, mediated by the
mef
(A) gene, was the most common macrolide resistance mechanism. Four macrolide-resistant isolates had mutations in rRNA or ribosomal protein L22.
Tanshinone (
Salviae miltiorrhizae
Extract) Preparations Attenuate Aminoglycoside-Induced Free Radical Formation In Vitro and Ototoxicity In Vivo
Authors: Wang Ai-Mei , Sha Su-Hua , Lesniak Wojciech , Schacht Jochen
Published: May 2003

Antioxidant therapy protects against aminoglycoside-induced ototoxicity in animal models. A clinically suitable antioxidant must not affect the therapeutic efficacy of aminoglycosides or exhibit any side effects of its own. In addition, the treatment should be inexpensive and convenient in order to be implemented in developing countries where the use of aminoglycosides is most common. Standardized
Salviae miltiorrhizae
extracts (Danshen) are used clinically in China and contain diterpene quinones and phenolic acids with antioxidant properties. We combined in vitro and in vivo approaches to investigate the effect of a clinically approved injectable Danshen solution on aminoglycoside-induced free radical generation and ototoxicity. In vitro, Danshen inhibited gentamicin-dependent lipid peroxidation (formation of conjugated dienes from arachidonic acid), as well as the gentamicin-catalyzed formation of superoxide (in a lucigenin-based chemiluminescence assay) and hydroxyl radicals (oxidation of N,N-dimethyl-
p
-nitrosoaniline). Danshen extracts were then administered to adult CBA mice receiving concurrent treatment with kanamycin (700 mg/kg of body weight twice daily for 15 days). Auditory threshold shifts induced by kanamycin (approximately 50 dB) were significantly attenuated. Danshen did not reduce the levels in serum or antibacterial efficacy of kanamycin. These results suggest that herbal medications may be a significantly underexplored source of antidotes for aminoglycoside ototoxicity. Such traditional medicines are widely used in many developing countries and could become an easily accepted and inexpensive protective therapy.
Effects of Pyrimidine and Purine Analog Combinations in the Duck Hepatitis B Virus Infection Model
Authors: Seignères Béatrice , Martin Perrine , Werle Bettina , Schorr Olivier , Jamard Catherine , Rimsky Laurence , Trépo Christian , Zoulim Fabien
Published: May 2003

To design new strategies of antiviral therapy for chronic hepatitis B, we have evaluated the antiviral activity of the combination of amdoxovir (DAPD), emtricitabine [(−)FTC], and clevudine (l-FMAU) in the duck hepatitis B virus (DHBV) model. Using their triphosphate (TP) derivatives in a cell-free system expressing a wild-type active DHBV reverse transcriptase (RT), the three dual combinations exhibited a greater additive inhibitory effect on viral minus-strand DNA synthesis than the single drugs, according to the Bliss independence model. Both dual combinations with DAPD TP were the most efficient while the triple combination increased the inhibitory effect on the DHBV RT activity in comparison with the dual association, however, without additive effect. Postinoculation treatment of experimentally infected primary duck hepatocytes showed that dual and triple combinations potently inhibited viral DNA synthesis during treatment but did not inhibit the reinitiation of viral DNA synthesis after treatment cessation. Preinoculation treatment with the same combinations exhibited antiviral effects on intracellular viral DNA replication, but it was unable to prevent the initial covalently closed circular DNA (cccDNA) formation. Short-term in vivo treatment in acutely infected ducklings showed that the dual combinations were more-potent inhibitors of virus production than the single treatments, with thel-FMAU and FTC combination being the most potent. A longer administration ofl-FMAU and FTC for 4 weeks efficiently suppressed viremia and viral replication. However, no viral clearance from the liver was observed, suggesting that the enhanced antiviral effect of this combination was not sufficient for cccDNA suppression and HBV eradication from infected cells.
Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal Function
Authors: Tam Vincent H. , McKinnon Peggy S. , Akins Ronda L. , Drusano George L. , Rybak Michael J.
Published: May 2003

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL
CR
) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (
C
min
).
C
min
in this group was found to be 3.3 ± 3.6 mg/liter (mean and standard deviation), compared to 19.5 ± 21.5 mg/liter in patients with a CL
CR
of between 60 and 100 ml/min (
P
= 0.025) and 14.0 ± 11.5 mg/liter in patients with a CL
CR
of <60 ml/min (
P
= 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL
CR
were highly correlated (
P
= 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 × CL
CR
). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h
−1
, respectively. The time-concentration profiles for 1,000 patients (CL
CR
s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a
C
min
that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs ≤2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are ≥4 mg/liter), particularly when CL
CR
exceeds 120 ml/min.
Clinical Pharmacokinetics of Cefamandole and Ceftazidime Administered by Continuous Intravenous Infusion
Authors: Berkhout J. , Visser L. G. , van den Broek P. J. , van de Klundert J. A. M. , Mattie H.
Published: May 2003

In view of the results of animal studies as well as theoretical considerations, continuous administration of β-lactam antibiotics should be superior to intermittent administration because of the close relationship between efficacy and the duration of time in which the concentration of unbound antibiotics in plasma remains above the MIC. The aim of the present study was to establish the pharmacokinetic parameters of cefamandole and ceftazidime for patients receiving these cephalosporins by continuous infusion. The interindividual differences in the concentrations in plasma at the steady state were mainly attributable to variations in renal function, as estimated by the rate of creatinine clearance. Using these results, we derived formulas for both cephalosporins that can be used to determine on an individual basis the total daily dose needed to obtain a therapeutic concentration in plasma. These formulas were tested with a group of subsequent patients and proved to be practical and fairly reliable. For some patients, a correction for a possible underestimation of the renal clearance at presentation might be required.
Antimicrobial Resistance in Respiratory Tract
Streptococcus pneumoniae
Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002
Authors: Zhanel George G. , Palatnick Lorraine , Nichol Kimberly A. , Bellyou Tracy , Low Don E. , Hoban Daryl J.
Published: May 2003

A total of 6,991 unique patient isolates of
Streptococcus pneumoniae
were collected from October 1997 to June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among these isolates, 20.2% were penicillin nonsusceptible, with 14.6% being penicillin intermediate (MIC, 0.12 to 1 μg/ml) and 5.6% being penicillin resistant (MIC, ≥2 μg/ml). The proportion of high-level penicillin-resistant
S. pneumoniae
isolates increased from 2.4 to 13.8% over the last 3 years of the study, and the proportion of multidrug-resistant
S. pneumoniae
isolates increased from 2.7 to 8.8% over the 5-year period. Resistant rates (intermediate and resistant) among non-β-lactam agents were as follows: macrolides, 9.6 to 9.9%; clindamycin, 3.8%; doxycycline, 5.5%; chloramphenicol, 3.9%; and trimethoprim-sulfamethoxazole, 19.0%. Rates of resistance to non-β-lactam agents were higher among penicillin-resistant strains than among penicillin-susceptible strains. No resistance to vancomycin or linezolid was observed; however, 0.1% intermediate resistance to quinupristin-dalfopristin was observed. The rate of macrolide resistance (intermediate and resistant) increased from 7.9 to 11.1% over the 5 years. For the fluoroquinolones, the order of activity based on the MICs at which 50% of isolates are inhibited (MIC
50
s) and the MIC
90
s was gemifloxacin > clinafloxacin > trovafloxacin > moxifloxacin > grepafloxacin > gatifloxacin > levofloxacin > ciprofloxacin. The investigational compounds ABT-773 (MIC
90
, 0.008 μg/ml), ABT-492 (MIC
90
, 0.015 μg/ml), GAR-936 (tigecycline; MIC
90
, 0.06 μg/ml), and BMS284756 (garenoxacin; MIC
90
, 0.06 μg/ml) displayed excellent activities. Despite decreases in the rates of antibiotic consumption in Canada over the 5-year period, the rates of both high-level penicillin-resistant and multidrug-resistant
S. pneumoniae
isolates are increasing in Canada.