bluuebunny/crossref_metadata_2025 huggingface dataset:
Material‐specific analysis using coherent‐scatter imaging
Authors: Batchelar Deidre L. , Cunningham Ian A.
Published: October 2002

Coherent‐scatter computed tomography (CSCT) is a novel imaging method we are developing to produce cross‐sectional images based on the low‐angle (<10°) scatter properties of tissue. At diagnostic energies, this scatter is primarily coherent with properties dependent upon the molecular structure of the scatterer. This facilitates the production of material‐specific maps of each component in a conglomerate. Our particular goal is to obtain quantitative maps of bone‐mineral content. A diagnostic x‐ray source and image intensifier are used to acquire scatter patterns under first‐generation CT geometry. An accurate measurement of the scatter patterns is necessary to correctly identify and quantify tissue composition. This requires corrections for exposure fluctuations, temporal lag in the intensifier, and self‐attenuation within the specimen. The effect of lag is corrected using an approximate convolution method. Self‐attenuation causes a cupping artifact in the CSCT images and is corrected using measurements of the transmitted primary beam. An accurate correction is required for reliable density measurements from material‐specific images. The correction is shown to introduce negligible noise to the images and a theoretical expression for CSCT image SNR is confirmed by experiment. With these corrections, the scatter intensity is proportional to the number of scattering centers interrogated and quantitative measurements of each material are obtained. Results are demonstrated using both a series of poly(methyl methacrylate) (PMMA) sheets of increasing thickness (2–12 mm) and a series of 5 acrylic rods containing varying amounts of hydroxyapatite simulating the physiological range of bone‐mineral density (BMD) found in trabecular bone. The excellent agreement between known and measured BMD demonstrates the viability of CSCT as a tool for densitometry.
Pulsed‐microwave‐induced thermoacoustic tomography: Filtered backprojection in a circular measurement configuration
Authors: Xu Minghua , Wang Lihong V.
Published: October 2002

Our study on pulsed‐microwave‐induced thermoacoustic tomography in biological tissues is presented. A filtered backprojection algorithm based on rigorous theory is used to reconstruct the cross‐sectional image from a thermoacoustic measurement in a circular configuration that encloses the sample under study. Specific details describing the measurement of thermoacoustic waves and the implementation of the reconstruction algorithm are discussed. A two‐dimensional (2D) phantom sample with 2 mm features can be imaged faithfully. Through numerical simulation, the full width half‐maximum (FWHM) of the point‐spread function (PSF) is calculated to estimate the spatial resolution. The results demonstrate that the circular measurement configuration combined with the filtered backprojection method is a promising technique for detecting small tumors buried in biological tissues by utilizing microwave absorption contrast and ultrasound spatial resolution (∼mm).
Output variation from an intensity modulating dynamic collimator
Authors: Hossain Murshed , Houser Christopher J. , Galvin James M.
Published: October 2002

Intensity modulated radiation therapy (IMRT) offers a method of delivering radiation dose conforming to the shape of targets while minimizing the dose to the surrounding tissue and nearby critical organs. One popular device is the NOMOS MIMiC Collimator coupled to the CORVUS treatment planning system. The MIMiC collimator, mounted on a linac head, opens and closes one or more of its 40 small leaves as determined by the planner while the linac delivers radiation and the gantry rotates. This dynamic IMRT allows the intensity to be modulated yielding a highly conformal dose distribution. However, the dose output becomes a function of the detailed manner in which the leaves open and close, since the opening and closing are not instantaneous. We investigate the effect of switch rates and delay in the open/close events on the output profiles. The output is enhanced as the switch rate increases. The enhancement factor at any point of measurement is dependent on its distance from the central plane. We interpret these variations in terms of a simple model, which includes the effect of leaf travel time during the process of opening and closing. We also include the time delay in establishing the specified pressure in the pneumonic device, which controls the opening and closing of the leaves. The information presented here offers a means for incorporating these output changes into the planning system. This may avoid the current situation where many patient plans need to be renormalized based on the actual measurement taken during the delivery of the specified intensity pattern to a phantom.
IMRT verification by three‐dimensional dose reconstruction from portal beam measurements
Authors: Partridge M. , Ebert M. , Hesse B‐M.
Published: October 2002

A method of reconstructing three‐dimensional,in vivodose distributions delivered by intensity‐modulated radiotherapy (IMRT) is presented. A proof‐of‐principle experiment is described where an inverse‐planned IMRT treatment is delivered to an anthropomorphic phantom. The exact position of the phantom at the time of treatment is measured by acquiring megavoltage CT data with the treatment beam and a research prototype, flat‐panel, electronic portal imaging device. Immediately following CT imaging, the planned IMRT beams are delivered using the multiple‐static field technique. The delivered fluence is sampled using the same detector as for the CT data. The signal measured by the portal imaging device is converted to primary fluence using an iterative phantom‐scatter estimation technique. This primary fluence is back‐projected through the previously acquired megavoltage CT model of the phantom, with inverse attenuation correction, to yield an input fluence map. The input fluence maps are used to calculate a “reconstructed” dose distribution using the same convolution/superposition algorithm as for the original planning dose calculation. Both relative and absolute dose reconstructions are shown. For the relative measurements, individual beam weights are taken from measurements but the total dose is normalized at the reference point. The absolute dose reconstructions do not use any dosimetric information from the original plan. Planned and reconstructed dose distributions are compared, with the reconstructed relative dose distribution also being compared to film measurements.
Practical aspects of functional MRI (NMR Task Group #8)
Authors: Price Ronald R. , Allison Jerry , Massoth Richard J. , Clarke Geoffrey D. , Drost Dick J.
Published: October 2002

Functional MR imaging (fMRI) based upon the Blood Oxygen Level Dependent (BOLD) effect is currently an important new tool for understanding basic brain function and specifically allowing the correlation of physiological activity with anatomical location without the use of ionizing radiation. The clinical role of fMRI is still being defined and is the subject of much research activity. In this report we present the underlying physical, technical and mathematical principals of BOLD fMRI along with descriptions of typical applications. Our purpose in this report is to provide, in addition to basic principles, an insight into the aspects of BOLD imaging, which may be used by the medical physicist to assist in the implement of fMRI procedures in either a hospital or research environment.
Integration of digital fluoroscopy with CT‐based radiation therapy planning of lung tumors
Authors: Ruschin Mark , Sixel Katharina E.
Published: October 2002

Radiation dose escalation may be a means to increase the local control rate of inoperable lung tumors. Treatment plans involve the creation of a uniform planning target volume (PTV) to ensure proper coverage despite patient breathing and setup error. This may lead to unnecessary radiation of normal tissue in shallow breathers or target underdosing for patients with excess internal motion. Therefore, the nature of tumor motion for each patient should be measured in 3D, something that cannot be done with CT alone. We have developed a method that acquires 2D real‐time fluoroscopic images (loops) and coregisters them with 2D digitally reconstructed radiographs (DRR) formed from the CT scan. The limitations of CT to encompass motion can be overcome by merging the two modalities together. The accuracy of the coregistration method is tested with a stationary grid of radio‐opaque markers at various spatial positions. The in‐plane (at‐depth) displacement between markers on the fluoroscopic image versus the DRR varies with position across the image due to slight misalignments between the x‐ray source used in fluoroscopy and the virtual source used for the DRR relative to the test object. At clinically relevant positions, the maximum, measured in‐plane displacement, is 1.1 mm. The method is applied to the thorax of an anthropomorphic phantom and a good fit is observed between the appearances of the bony anatomical structures on the coregistered image. Finally, a series of motion measurements are carried out on two oscillating cylindrical objects. The degree of motion as measured by fluoroscopy is accurate to within 1.0 mm, whereas the DRR is inconsistent in predicting motion. The coregistration of fluoroscopic loops with the DRR shows at what point within the oscillation the DRR fails to encompass motion. For any treatment site involving target motion, this real‐time imaging is a useful asset in the planning stage.
Polar and axial vectors versus quaternions
Authors: Silva Cibelle Celestino , de Andrade Martins Roberto
Published: October 2002

Vectors and quaternions are quite different mathematical quantities because they have different symmetry properties. Gibbs and Heaviside created their vector system starting from the quaternion system invented by Hamilton. They identified a pure quaternion as a vector and introduced some changes in the product of two vectors defined by Hamilton without realizing that the scalar product and vector product cannot be interpreted as the scalar part and vector part of the quaternion product. Toward the end of the 19th century some authors realized that there was an incompatibility between the vector and quaternion formalisms, but the central problem was not altogether clear. This paper will show that the main difficulty arose from Hamilton’s contradictory use of i, j, and k both as versors and as vectors.
A simple laser cooling and trapping apparatus for undergraduate laboratories
Authors: Mellish Angela S. , Wilson Andrew C.
Published: October 2002

We present detailed instructions for the construction of a pyramidal-style laser cooling and trapping apparatus. This scheme requires only a single beam, rather than the three pairs of orthogonal beams of the standard magneto-optical trap, which greatly simplifies the geometry and substantially reduces the cost. The trap is based largely on low-cost commercially available items and is simple to construct. It is remarkably insensitive to alignment and reliable to operate. Using a single laser beam with an intensity of 1.3 mW/cm2 we cool and trap more than 4 million rubidium atoms.
Wavefronts and waveforms in deep-water sound propagation
Authors: Tindle Chris T.
Published: October 2002

A new method of calculating waveforms in underwater sound propagation is presented. The method is based on a Hankel transform-generalized Wentzel–Kramers–Brillouin (WKB) solution of the wave equation. The resulting integral leads to a new form of ray theory which is valid at relatively low frequencies and allows evaluation of the acoustic field on both the illuminated and shadow sides of caustics and at cusps where two caustics meet to form a focus. The integral is evaluated by stationary phase methods for the appropriate number of stationary points. Rays of nearby launch angle which have a travel time difference less than a quarter period must be considered together. The description of all other ray arrivals corresponds to simple ray theory. The phase, amplitude, and travel time of broadband acoustic pulses are obtainable directly from a simple graph of ray travel time as a function of depth at a given range. The method can handle range dependence but is illustrated here in long-distance propagation in deep water where the ray paths do not pass close to surface or bottom. The method is fast and gives close agreement with normal-mode calculations. The field on the shadow side of a caustic is properly given in terms of rays with complex launch angles, but good approximations can be obtained without the need to find complex rays.
The relative detectability for mice of gaps having different ramp durations at their onset and offset boundaries
Authors: Ison James R. , Castro Jason , Allen Paul , Virag Tracy M. , Walton Joseph P.
Published: October 2002

The effect on gap detectability of varying noise fall time (FT) and rise time (RT) of the gap boundary ramps was examined in mice using reflex modification audiometry, measuring inhibition of acoustic startle reflexes by variously shaped gaps just preceding reflex expression. In experiment 1 (n=12) inhibition increased up to near-asymptotic values with longer FT (0, 1, 2, 3, 5, or 10 ms) and QT (quiet time, 0 to 13 ms), with a 2:1 trade-off between FT and QT. In experiment 2 (n=24) inhibition increased for any RT above 0 ms (2, 3, 5, or 7 ms) if QT=1 ms, but diminished with increased RT when QT=3 or 8 ms. Enhanced detectability for subthreshold gaps by longer ramps results from their extending the apparent gap duration. The negative effect of increased RT for threshold gaps suggests the importance for gap detection of the stronger neural responses to sharp edges at the end of the gap shown previously in the mouse inferior colliculus. These effects are specific to gaps: inhibition for fixed (70-dB SPL) or varied level pulses (30 to 60 dB) was unaffected by varying the ramped edges (experiments 3 and 4, n=9).
Free molecular sound propagation
Authors: Sharipov F. , Marques W. , Kremer G. M.
Published: October 2002

The sound propagation through a gas in the free-molecular regime is studied on the basis of the linearized collisionless Boltzmann equation. The two principal quantities that characterize the sound propagation, namely the phase and amplitude of the perturbation, are determined by taking into account the influence of the receptor. It is shown that at a small distance between the source and the receptor the presence of the last changes qualitatively the sound characteristics. Two phase velocities are introduced: a differential and an integral, which are different in the free molecular regime.
Three-dimensional propagation effects near the mid-Atlantic Bight shelf break (L)
Authors: Smith Kevin B. , Miller Chris W. , D’Agostino Anthony F. , Sperry Brian , Miller James H. , Potty Gopu R.
Published: October 2002

Significant three-dimensional (3-D) environmental variability exists in the vicinity of the shelf break along the mid-Atlantic Bight. This study examines the influence of azimuthal coupling due to this variability on acoustic propagation in this region. Numerical studies employing a 3-D ray code, a hybrid ray-mode code, and a 3-D parabolic equation model are used to study the significance of azimuthal coupling on various propagation paths. These paths include up-slope, slant-slope, and cross-slope propagation. The numerical analysis suggests that, for the propagation ranges less than 60 km examined, the influence of azimuthal coupling is negligible compared to the inherent uncertainty in the environment itself.
Acoustic intensity, impedance and reflection coefficient in the human ear canal
Authors: Farmer-Fedor B. L. , Rabbitt R. D.
Published: October 2002

The sound power per unit cross-sectional area was determined in human ear canals using a new method based on measuring the pressure distribution (P) along the length of variable cross-section acoustic waveguides. The technique provides the pressure/power reflection coefficients (R/R) as well as the acoustic intensity of the nonplanar incident wave (I+, the acoustic input to the ear) and the nonplanar outgoing wave (I−, the acoustic output of the ear). Results were compared to the classical acoustic impedance (Z) and associated plane-wave power reflection coefficient (RZ). Performance of the method was investigated theoretically using horn equation simulations and evaluated experimentally using pressure data recorded in nonuniform waveguides. The method was applied in normal-hearing young adults to determine ear-canal position- and frequency-dependence of I±, ℛ, and RZ using random phase broadband stimuli (1–15 kHz; ∼75 dB SPL). Reflection coefficient (ℛ) measurements at two different locations within individual human ear canals exhibited a position dependence averaging ΔR∼0.1 (over 6 mm distance)—a difference consistent with predictions of inviscid acoustics in nonuniform waveguides. Since this position dependence was relatively small, an “optimized” position-independent reflection coefficient was defined to facilitate practical application and intersubject comparisons.
Distribution of risk factors for hearing loss: Implications for evaluating risk of occupational noise-induced hearing loss
Authors: Prince Mary M.
Published: October 2002

This paper presents an analysis of hearing threshold levels among 2066 white male workers employed in various U.S. industries studied in the 1968–72 NIOSH Occupational Noise and Hearing Survey (ONHS). The distribution of hearing threshold levels (HTL) is examined in relation to various risk factors (age, prior occupational noise, medical conditions) for hearing loss among a population of noise exposed and control (low noise-exposed) industrial workers. Previous analyses of a subset of these data from the ONHS focused on 1172 highly “screened” workers. An additional 894 male workers (609 noise-exposed and 285 controls), who were excluded for various reasons (i.e., nonoccupational noise exposure, otologic or medical conditions affecting hearing, prior occupational noise exposure) have been added to examine hearing loss in an unscreened population. Data are analyzed by age, duration of exposure, and sound level (8-h TWA) by individual test frequency. Results indicate that hearing threshold levels are higher among unscreened noise-exposed and control workers relative to screened workers. Analysis of risk factors such as nonoccupational noise exposure, medical conditions, and type of industry among unscreened controls indicated that these factors were not significantly associated with increased mean HTLs or risk of material impairment over and above what is expected due to age. Age-specific mean hearing threshold levels (and percentiles of the distribution) among the unscreened ONHS control population may be used as a comparison population of low-noise exposed white male industrial workers for evaluating the effectiveness of hearing conservation programs for workers less than 55 years of age. To make valid inferences regarding occupational noise-induced hearing loss, it is important to use hearing data from reference (control) populations that are similar with respect to the degree of subject screening, type of work force (blue vs white collar), and the distribution of other risk factors for hearing loss.
Ecological Effects of Climate Fluctuations
Authors: Stenseth Nils C. , Mysterud Atle , Ottersen Geir , Hurrell James W. , Chan Kung-Sik , Lima Mauricio
Published: October 2002

Climate influences a variety of ecological processes. These effects operate through local weather parameters such as temperature, wind, rain, snow, and ocean currents, as well as interactions among these. In the temperate zone, local variations in weather are often coupled over large geographic areas through the transient behavior of atmospheric planetary-scale waves. These variations drive temporally and spatially averaged exchanges of heat, momentum, and water vapor that ultimately determine growth, recruitment, and migration patterns. Recently, there have been several studies of the impact of large-scale climatic forcing on ecological systems. We review how two of the best-known climate phenomena—the North Atlantic Oscillation and the El Niño–Southern Oscillation—affect ecological patterns and processes in both marine and terrestrial systems.
Femtosecond Infrared Spectroscopy of Bacteriorhodopsin Chromophore Isomerization
Authors: Herbst Johannes , Heyne Karsten , Diller Rolf
Published: October 2002

The vibrational dynamics of the retinal chromophore all-trans–to–13-cis photoisomerization in bacteriorhodopsin has been studied with mid-infrared absorption spectroscopy at high time resolution (about 200 femtoseconds). After photoexcitation of light-adapted bacteriorhodopsin, the transient infrared absorption was probed in a broad spectral region, including vibrations with dominant C–C, C=C, and C=NH stretching mode amplitude. All photoproduct modes, especially those around 1190 reciprocal-centimeters that are indicative for a 13-cis configuration of the chromophore, rise with a time constant of ∼0.5 picosecond. The results presented give direct vibrational-spectroscopic evidence for the isomerization taking place within 0.5 picosecond, as has been suggested by previous optical femtosecond time-resolved experiments but questioned recently by picosecond time-resolved vibrational spectroscopy experiments.
Distinct Modes of Signal Recognition Particle Interaction with the Ribosome
Authors: Pool Martin R. , Stumm Joachim , Fulga Tudor A. , Sinning Irmgard , Dobberstein Bernhard
Published: October 2002

Signal recognition particle (SRP), together with its receptor (SR), mediates the targeting of ribosome-nascent chain complexes to the endoplasmic reticulum. Using protein cross-linking, we detected distinct modes in the binding of SRP to the ribosome. During signal peptide recognition, SRP54 is positioned at the exit site close to ribosomal proteins L23a and L35. When SRP54 contacts SR, SRP54 is rearranged such that it is no longer close to L23a. This repositioning may allow the translocon to dock with the ribosome, leading to insertion of the signal peptide into the translocation channel.
White Collar-1, a DNA Binding Transcription Factor and a Light Sensor
Authors: He Qiyang , Cheng Ping , Yang Yuhong , Wang Lixing , Gardner Kevin H. , Liu Yi
Published: October 2002

Blue light regulates many physiological processes in fungi, but their photoreceptors are not known. In
Neurospora crassa
, all light responses depend on the Per-Arnt-Sim (PAS) domain–containing transcription factor
white collar–1
(
wc-1
). By removing the WC-1 light, oxygen, or voltage domain, a specialized PAS domain that binds flavin mononucleotide in plant phototropins, we show that light responses are abolished, including light entrainment of the circadian clock. However, the WC-1–mediated dark activation of
frq
remains normal in this mutant, and the circadian clock can be entrained by temperature. Furthermore, we demonstrate that the purified
Neurospora
WC-1–WC-2 protein complex is associated with stoichiometric amounts of the chromophore flavin-adenine dinucleotide. Together, these observations suggest that WC-1 is the blue-light photoreceptor for the circadian clock and other light responses in
Neurospora
.
Sexual Selection, Temperature, and the Lion's Mane
Authors: West Peyton M. , Packer Craig
Published: October 2002

The mane of the African lion (
Panthera leo
) is a highly variable trait that reflects male condition and ambient temperature. We examined the consequences of this variation in a long-term study of lions in the Serengeti National Park, Tanzania. Mane darkness indicates nutrition and testosterone and influences both female choice and male-male competition. Mane length signals fighting success and only appears to influence male-male assessment. Dark-maned males enjoy longer reproductive life-spans and higher offspring survival, but they suffer higher surface temperatures, abnormal sperm, and lower food intake during hot months of the year. Maned males are hotter than females, and males have lighter and/or shorter manes in hotter seasons, years, and habitats. This phenotypic plasticity suggests that the mane will respond to forecasted increases in ambient temperature.
Crystallographic Evidence for a Free Silylium Ion
Authors: Kim Kee-Chan , Reed Christopher A. , Elliott Douglas W. , Mueller Leonard J. , Tham Fook , Lin Lijun , Lambert Joseph B.
Published: October 2002

Evidence for a three-coordinate silyl cation is provided by the crystal structure of [(Mes)
3
Si][H-CB
11
Me
5
Br
6
]·C
6
H
6
(where Mes is 2,4,6-trimethylphenyl). Free (Mes)
3
Si
+
cations are well separated from the carborane anions and benzene solvate molecules.
Ortho
-methyl groups of the mesityl substituents shield the silicon atom from the close approach of nucleophiles, while remaining innocent as significant ligands themselves. The silicon center is three-coordinate and planar. The downfield
29
Si nuclear magnetic resonance chemical shift in the solid state (226.7 parts per million) is almost identical to that in benzene solution and in “gas phase” calculations, indicating that three-coordination can be preserved in all phases.
S-Nitrosylation of Matrix Metalloproteinases: Signaling Pathway to Neuronal Cell Death
Authors: Gu Zezong , Kaul Marcus , Yan Boxu , Kridel Steven J. , Cui Jiankun , Strongin Alex , Smith Jeffrey W. , Liddington Robert C. , Lipton Stuart A.
Published: October 2002

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of neurodegenerative diseases and stroke. However, the mechanism of MMP activation remains unclear. We report that MMP activation involves S-nitrosylation. During cerebral ischemia in vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated MMP-9 in vitro and induced neuronal apoptosis. Mass spectrometry identified the active derivative of MMP-9, both in vitro and in vivo, as a stable sulfinic or sulfonic acid, whose formation was triggered by S-nitrosylation. These findings suggest a potential extracellular proteolysis pathway to neuronal cell death in which S-nitrosylation activates MMPs, and further oxidation results in a stable posttranslational modification with pathological activity.
Mechanisms of Adaptation in a Predator-Prey Arms Race: TTX-Resistant Sodium Channels
Authors: Geffeney Shana , Brodie Edmund D. , Ruben Peter C. , Brodie Edmund D.
Published: October 2002

Populations of the garter snake
Thamnophis sirtalis
have evolved geographically variable resistance to tetrodotoxin (TTX) in a coevolutionary arms race with their toxic prey, newts of the genus
Taricha
. Here, we identify a physiological mechanism, the expression of TTX-resistant sodium channels in skeletal muscle, responsible for adaptive diversification in whole-animal resistance. Both individual and population differences in the ability of skeletal muscle fibers to function in the presence of TTX correlate closely with whole-animal measures of TTX resistance. Demonstration of individual variation in an essential physiological function responsible for the adaptive differences among populations is a step toward linking the selective consequences of coevolutionary interactions to geographic and phylogenetic patterns of diversity.
The Ascetic and the Vixen
Authors: Kotkin Stephen
Published: October 2002

Sakharov
A Biography. Richard Lourie. Brandeis University Press (University Press of New England), Hanover, NH, 2002. 495 pp. $30, £21. ISBN 1-58465-207-1.

Although this account of the Soviet physicist and dissident does not focus on science, Lourie shows that his subject's varied life was grounded on a consistent set of beliefs and practices.
Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization
Authors: Lassus Patrice , Opitz-Araya Ximena , Lazebnik Yuri
Published: October 2002

A current view is that cytotoxic stress, such as DNA damage, induces apoptosis by regulating the permeability of mitochondria. Mitochondria sequester several proteins that, if released, kill by activating caspases, the proteases that disassemble the cell. Cytokines activate caspases in a different way, by assembling receptor complexes that activate caspases directly; in this case, the subsequent mitochondrial permeabilization accelerates cell disassembly by amplifying caspase activity. We found that cytotoxic stress causes activation of caspase-2, and that this caspase is required for the permeabilization of mitochondria. Therefore, we argue that cytokine-induced and stress-induced apoptosis act through conceptually similar pathways in which mitochondria are amplifiers of caspase activity rather than initiators of caspase activation.
20th- to 21st-Century Technological Challenges in Soft Coatings
Authors: Matheson Robert R.
Published: October 2002

Coatings are among the most ancient technologies of humankind. Relatively soft coatings comprising organic materials such as blood, eggs, and extracts from plants were in use more than 20,000 years ago, and coating activity has been continuously practiced since then with gradually improving materials and application techniques. The fundamental purposes of protecting and/or decorating substrates have remained ubiquitous across all the centuries and cultures of civilization. This article attempts to extrapolate the long tale of change in soft coating technology from its current state by identifying some key problems that attract research and development efforts as our 21st century begins.
Biodegradable Polymers for the Environment
Authors: Gross Richard A. , Kalra Bhanu
Published: October 2002

Biodegradable polymers are designed to degrade upon disposal by the action of living organisms. Extraordinary progress has been made in the development of practical processes and products from polymers such as starch, cellulose, and lactic acid. The need to create alternative biodegradable water-soluble polymers for down-the-drain products such as detergents and cosmetics has taken on increasing importance. Consumers have, however, thus far attached little or no added value to the property of biodegradability, forcing industry to compete head-to-head on a cost-performance basis with existing familiar products. In addition, no suitable infrastructure for the disposal of biodegradable materials exists as yet.
N-Alkyl Urea Hydroxamic Acids as a New Class of Peptide Deformylase Inhibitors with Antibacterial Activity
Authors: Hackbarth Corinne J. , Chen Dawn Z. , Lewis Jason G. , Clark Kirk , Mangold James B. , Cramer Jeffrey A. , Margolis Peter S. , Wang Wen , Koehn Jim , Wu Charlotte , Lopez S. , Withers George , Gu Helen , Dunn Elina , Kulathila R. , Pan Shi-Hao , Porter Wilma L. , Jacobs Jeff , Trias Joaquim , Patel Dinesh V. , Weidmann Beat , White Richard J. , Yuan Zhengyu
Published: October 2002

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P1′ site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors withN-alkyl urea at the P1′ site. Compounds with MICs of ≤4 μg/ml against gram-positive and gram-negative pathogens, includingStaphylococcusaureus,Streptococcuspneumoniae, andHaemophilusinfluenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC50s) forEscherichiacoliNi-PDF were ≤0.1 μM, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC50s of consistently >200 μM for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 Å. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. TheseN-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.
Different Levels of Genetic Homogeneity in Vancomycin-Resistant and -Susceptible
Enterococcus faecium
Isolates from Different Human and Animal Sources Analyzed by Amplified-Fragment Length Polymorphism
Authors: Bruinsma Nienke , Willems Rob J. L. , van den Bogaard Anthony E. , van Santen-Verheuvel Marga , London Nancy , Driessen Christel , Stobberingh Ellen E.
Published: October 2002

The genetic relationship among fecal vancomycin-resistant
Enterococcus faecium
(VREF) and vancomycin-susceptible
E. faecium
(VSEF) isolates (
n
= 178) from the same populations of pigs, human healthy volunteers, and hospitalized patients (from The Netherlands) and chickens (from The Netherlands and Greece) was studied by amplified-fragment length polymorphism (AFLP). The majority of VREF isolates from pigs, healthy volunteers, and hospitalized patients grouped together (genetic similarity, ≥65%). In a previous AFLP study by our group the VREF isolates from hospitalized patients grouped separately, most likely because these were clinical and not fecal isolates as in the present study. Furthermore, VSEF isolates from humans and pigs were found much more genetically diverse than VREF isolates, whereas VREF and VSEF isolates from chickens clustered together in a separate genogroup (genetic similarity, ≥65%), a pattern clearly distinct from the patterns for human and pig isolates. The present study suggests that pigs are a more important source of VREF for humans than chickens and that human- and pig-derived VSEF isolates seem much more heterogeneous than VREF isolates.
The LisRK Signal Transduction System Determines the Sensitivity of
Listeria monocytogenes
to Nisin and Cephalosporins
Authors: Cotter Paul D. , Guinane Caitriona M. , Hill Colin
Published: October 2002

The
Listeria monocytogenes
two-component signal transduction system, LisRK, initially identified in strain LO28, plays a significant role in the virulence potential of this important food-borne pathogen. Here, it is shown that, in addition to its major contribution in responding to ethanol, pH, and hydrogen peroxide stresses, LisRK is involved in the ability of the cell to tolerate important antimicrobials used in food and in medicine, e.g., the lantibiotic nisin and the cephalosporin family of antibiotics. A Δ
lisK
mutant (lacking the LisK histidine kinase sensor component) displays significantly enhanced resistance to the lantibiotic nisin, a greatly enhanced sensitivity to the cephalosporins, and a large reduction in the expression of three genes thought to encode a penicillin-binding protein, another histidine kinase (other than LisK), and a protein of unknown function. Confirmation of the role of LisRK was obtained when the response regulator, LisR, was overexpressed using both constitutive and inducible (nisin-controlled expression) systems. Under these conditions we observed a reversion of the Δ
lisK
mutant to wild-type growth kinetics in the presence of nisin. It was also found that overexpression of LisR complemented the reduced expression of two of the aforementioned genes. These results demonstrate the important role of LisRK in the response of
L. monocytogenes
to a number of antimicrobial agents.
Frequency of Disinfectant Resistance Genes and Genetic Linkage with β-Lactamase Transposon Tn552among Clinical Staphylococci
Authors: Sidhu Maan Singh , Heir Even , Leegaard Truls , Wiger Karianne , Holck Askild
Published: October 2002

A total of 61 strains ofStaphylococcus aureusand 177 coagulase-negative staphylococcal strains were isolated from the blood of patients with bloodstream infections and from the skin of both children under cancer treatment and human immunodeficiency virus-positive patients. The MIC analyses revealed that 118 isolates (50%) were resistant to quaternary ammonium compound-based disinfectant benzalkonium chloride (BC). The frequencies of resistance to a range of antibiotics were significantly higher among BC-resistant staphylococci than among BC-sensitive staphylococci. Of 78 BC-resistant staphylococcal isolates, plasmid DNA from 65 (83%), 2 (3%), 43 (55%), and 15 (19%) isolates hybridized toqacAor -B(qacA/B),qacC,blaZ, andtetKprobes, respectively. TheqacA/BandblaZprobes hybridized to the same plasmid in 19 (24%) staphylococcal strains. The plasmids harboring bothqacA/BandblaZgenes varied from approximately 20 to 40 kb. TheStaphylococcus epidermidisFol62 isolate, harboring multiresistance plasmid pMS62, containedqacA/BandblaZtogether withtetK. Molecular and genetic studies indicated different structural arrangements ofblaZandqacA/B, including variable intergenic distances and transcriptional directions of the two genes on the same plasmid within the strains. The different organizations may be due to the presence of various genetic elements involved in cointegration, recombination, and rearrangements. These results indicate thatqacresistance genes are common and that linkage between resistance to disinfectants and penicillin resistance occurs frequently in clinical isolates in Norway. Moreover, the higher frequency of antibiotic resistance among BC-resistant strains indicates that the presence of either resistance determinant selects for the other during antimicrobial therapy and disinfection in hospitals.
Penciclovir Susceptibilities of Herpes Simplex Virus Isolates from Patients Using Penciclovir Cream for Treatment of Recurrent Herpes Labialis
Authors: Sarisky Robert T. , Bacon Teresa , Boon Ron , Locke Leslie , Nguyen Tammy T. , Leary Jeffry , Esser Klaus , Saltzman Robin
Published: October 2002

The antiherpesvirus agent penciclovir (PCV) shares an identical activation pathway and a similar mode of action with acyclovir (ACV). However, since PCV represents a relatively recent treatment option, the clinical resistance profile to PCV is less well known. A susceptibility program was established to assess the resistance profile for serial herpes simplex virus isolates from immunocompetent patients with recurrent herpes labialis obtained throughout a 4-day period of treatment with topical PCV (1% cream) or a placebo. Two isolates (2 of 1,035 [0.19%]), representing 0.34% of the patients (2 of 585), were confirmed to be PCV-resistant (Pcv
r
) herpes simplex virus type 1 by a plaque reduction assay in MRC-5 cells. These two viruses were highly resistant to PCV (50% inhibitory concentrations [IC
50
s], >55 μg/ml) and were isolated less than 17 h after the start of patient-initiated treatment. However, subsequent isolates on days 2 and 3 from these patients were completely susceptible to PCV (IC
50
s, <2.0 μg/ml). Thus, it is not clear whether the resistance to PCV for these two early-treatment isolates was directly associated with the 17 h of PCV treatment; several possible explanations are discussed. In an analysis of the distribution of IC
50
differences between the first and last isolates, there were three patients with minor IC
50
increases in the PCV-treated population and one in the placebo-treated group, although statistically, only the latter was an outlier. No patients were found to have Pcv
r
virus at the end of acute treatment, regardless of treatment group. Overall, the prevalence of Pcv
r
was found to be similar to the 0.3% Acv
r
reported for immunocompetent, untreated populations.
Comparative Study of Mechanisms of Herpes Simplex Virus Inactivation by Sodium Lauryl Sulfate and
n
-Lauroylsarcosine
Authors: Piret Jocelyne , Roy Sylvie , Gagnon Mylène , Landry Sébastien , Désormeaux André , Omar Rabeea F. , Bergeron Michel G.
Published: October 2002

The mechanisms of herpes simplex virus (HSV) inactivation by sodium lauryl sulfate (SLS) and
n
-lauroylsarcosine (LS), two anionic surfactants with protein denaturant potency, have been evaluated in cultured cells. Results showed that pretreatment of HSV type 1 (HSV-1) strain F and HSV-2 strain 333 with either surfactant inhibited, in a concentration- and time-dependent manner, their infectivities on Vero cells. SLS was a more potent inhibitor of HSV-2 strain 333 infectivity than LS with respect to the concentration (4.8-fold lower) and time (2.4-fold shorter) required to completely inactivate the virus. No inhibition of both herpesvirus strains infectivities was observed when Vero cells were pretreated with either surfactant. LS prevented the binding of HSV-2 strain 333 to cells without affecting the stable attachment and the rate of penetration into cells, whereas SLS exerted the opposite effect. Both SLS and LS inhibited, in a concentration-dependent manner, the HSV-2 strain 333-induced cytopathic effect, probably by affecting newly synthesized virions that come into contact with surfactant molecules present in culture medium. The pretreatment of HSV-2 strain 333 with specific combinations of SLS and LS concentrations inhibited the viral infectivity in a synergistic manner and resulted in only a small increase in their toxicities for exponentially growing Vero cells compared with that caused by each compound alone. Taken together, these results suggest that SLS and LS, alone or combined, could represent potent candidates as microbicides in topical vaginal formulations to prevent the transmission of herpes and possibly other pathogens that cause sexually transmitted diseases, including human immunodeficiency virus type 1.
Phase I Dose Escalation Trial Evaluating the Pharmacokinetics, Anti-Human Cytomegalovirus (HCMV) Activity, and Safety of 1263W94 in Human Immunodeficiency Virus-Infected Men with Asymptomatic HCMV Shedding
Authors: Lalezari Jacob P. , Aberg Judith A. , Wang Laurene H. , Wire Mary Beth , Miner Richard , Snowden Wendy , Talarico Christine L. , Shaw Shuching , Jacobson Mark A. , Drew W. Lawrence
Published: October 2002

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,β-
l
-ribofuranosyl-1-H-benzimidazole] is a novel benzimidazole compound for treatment of human cytomegalovirus (HCMV) infection and disease, with potent in vitro activity against HCMV and good oral bioavailability. A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding. Subjects received one of six dosage regimens (100, 200, or 400 mg three times a day, or 600, 900, or 1,200 mg twice a day) or a placebo for 28 days. 1263W94 demonstrated linear PK, with steady-state plasma 1263W94 profiles predictable based on single-dose data. 1263W94 was rapidly absorbed following oral dosing, and values for the maximum concentration of the drug in plasma and the area under the concentration-time curve increased in proportion to the dose. 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log
10
PFU/ml among the four regimens evaluated for anti-HCMV activity. 1263W94 was generally well tolerated; taste disturbance was the most frequently reported adverse event over the 28-day dosing period.
Pharmacodynamic Assessment of Ertapenem (MK-0826) against
Streptococcus
pneumoniae
in a Murine Neutropenic Thigh Infection Model
Authors: Xuan Dawei , Banevicius Maryanne , Capitano Blair , Kim Myo-Kyoung , Nightingale Charles , Nicolau David
Published: October 2002

The objective of this study was to determine the susceptibility breakpoint of a new carbapenem, ertapenem (MK-0826), against
Streptococcus pneumoniae
strains based on bacterial density and survival studies in a murine thigh infection model. Sixteen
S. pneumoniae
isolates for which MICs ranged from 0.015 to 4.0 mg/liter were tested with neutropenic ICR mice. Animals were infected with bacteria at 10
5
to 10
6
CFU per thigh and were treated with ertapenem starting at 2 h postinfection for 4 days. Ertapenem was given subcutaneously at 50 mg/kg of body weight every 6 h, which simulates the human pharmacodynamic profile (in particular, the duration of time that the concentration of free drug remains above the MIC of 2 mg/liter). At 0 and 24 h postinfection, thighs were harvested for bacterial density determination. Survival was assessed during 4 days of therapy and 3 days after the therapy. A protein binding study was conducted with mice by use of the ultrafiltration method. Protein binding in mice was approximately 95%, which is comparable to that in humans. The average change in bacterial density ranged from −0.22 to −4.4 log CFU per thigh over 24 h compared to 0-h controls. The extent of microbial eradication was dependent on the MIC for the
S. pneumoniae
isolate. Substantial bactericidal activities (i.e., killing of approximately 2 log CFU per thigh) were consistently observed against isolates for which MICs were ≤2 mg/liter, which also resulted in nearly 100% survival during the 4 days of drug dosing and 3 days after the therapy. Less-pronounced and highly variable bactericidal activities were detected against isolates for which the MIC was 4 mg/liter. Substantial enhancement in bactericidal activity was observed for CBA/J mice and is attributed to the contribution of the host defenses in the immunocompetent species. Assessment of the effectiveness of ertapenem by bacterial-density reduction over 24 h and by survival over 4 days of therapy in the murine thigh infection model reveals that the drug maintains maximal efficacy against
S. pneumoniae
isolates for which the MIC of this agent is ≤2 mg/liter.
Pharmacokinetic and Pharmacodynamic Profiles of Danofloxacin Administered by Two Dosing Regimens in Calves Infected withMannheimia(Pasteurella)haemolytica
Authors: Sarasola Patxi , Lees Peter , AliAbadi Fariborz Shojaee , McKellar Quintin A. , Donachie William , Marr Kate A. , Sunderland Simon J. , Rowan Tim G.
Published: October 2002

The pharmacokinetics and pharmacodynamics of danofloxacin in calves with inducedMannheimia(Pasteurella)haemolyticapneumonia were evaluated. Calves received either saline as an intravenous (IV) bolus or danofloxacin (0.738 mg/kg of body weight) administered as either a single IV bolus or a 36-h continuous IV infusion. Blood samples and bronchial secretions were collected before and at predetermined times over 48 h following the start of treatment. Calves were assessed clinically throughout, and lung consolidation was assessed at necropsy. Bronchial secretions and lung tissue were cultured forM. haemolytica. Bolus administration of danofloxacin produced a high maximum drug concentration-to-MIC ratio (Cmax:MIC) of 14.5 and a time period of 9.1 h when plasma danofloxacin concentrations exceeded the MIC (T>MIC). Following danofloxacin infusion, theCmax:MIC was low (2.3), with a longT>MIC (33.3 h). The area under the curve-to-MIC ratios were 43.3 and 49.1 for the bolus and infusion administrations, respectively. The single bolus of danofloxacin was more effective than the same dose administered by continuous infusion, as indicated by a significantly lower (P< 0.05) number of animals withM. haemolyticain bronchial secretions after treatment and lower rectal temperatures in the 24 h after the start of treatment. Thus, danofloxacin exhibited concentration-dependent antimicrobial activity in cattle with respiratory disease caused byM. haemolytica.