bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanoparticles for Thermal Cancer Therapy
Authors: Day Emily S. , Morton Jennifer G. , West Jennifer L.
Published: July 2009

Advances in nanotechnology are enabling many new diagnostic and therapeutic approaches in cancer. In this review, examples where nanoparticles are employed to induce localized heating within tumors are explored. Approaches to nanoparticle-mediated thermal therapy include absorption of infrared light, radio frequency ablation, and magnetically-induced heating. These approaches have demonstrated high efficacy in animal models, and two are already in human clinical trials.
Effect of Me2SO on Membrane Phase Behavior and Protein Denaturation of Human Pulmonary Endothelial Cells Studied by In Situ FTIR Spectroscopy
Authors: Spindler Ralf , Wolkers Willem F. , Glasmacher Birgit
Published: July 2009

Fourier transform infrared spectroscopy (FTIR) provides a unique technique to study membranes and proteins within their native cellular environment. FTIR was used here to study the effects of dimethyl sulfoxide (Me2SO) on membranes and proteins in human pulmonary endothelial cells (HPMECs). Temperature-dependent changes in characteristic lipid and protein vibrational bands were identified to reveal the effects of Me2SO on membrane phase behavior and protein stability. At Me2SO concentrations equal to or below 10% (v/v), Me2SO was found to decrease membrane conformational disorder. At higher Me2SO concentrations (15% v/v), however, membrane conformational disorder was found to be similar to that of cells in the absence of Me2SO. This effect was observed over a wide temperature range from 90°C down to −40°C. Me2SO had no clear effects on cellular proteins during freezing. During heating, however, Me2SO had a destabilizing effect on cellular proteins. In the absence of Me2SO, protein denaturation started at an onset temperature of 46°C, whereas at 15% Me2SO the onset temperature of protein denaturation decreased to 32°C. This implies that in the presence of Me2SO the onset temperature of protein denaturation is lower than the normal growth temperature of the cells, which could explain the well documented toxic effect of Me2SO at physiological temperatures. Me2SO destabilizes cellular proteins during heating and decreases membrane conformational disorder over a wide temperature range.
The Question of Thermal Waves in Heterogeneous and Biological Materials
Authors: Scott Elaine P. , Tilahun Muluken , Vick Brian
Published: July 2009

In the 1990s, there were two experimental studies that sparked a renewed interest in thermal wave behavior at the macroscale level. Both reported thermal relaxation times of 10 s or higher. However, no further experimental evidence of this behavior has been reported. Due to the extreme significance of these findings, the objectives of this study were to try to reproduce these earlier studies and offer an explanation for the outcome. These two previous studies, one using heterogeneous materials and one using bologna, were repeated following the experimental protocol provided in the studies as closely and as practically as possible. In both cases, the temperature response to a specified boundary condition was recorded. The results from the first set of experiments suggested that the thermal relaxation times presented in the previous study were actually the thermal lag expected from applying Fourier’s law, taking into account the uncertainty of the temperature sensor. In the second set of experiments, unlike the distinct jumps in temperature found previously, no indication of wave behavior was found. Here, the explanation for the previous results was more difficult to ascertain. Possible explanations include problems with either the experimental protocol or the temperature sensors used.
Photoacoustic Detection of Melanoma Micrometastasis in Sentinel Lymph Nodes
Authors: McCormack Devin , Al-Shaer Mays , Goldschmidt Benjamin S. , Dale Paul S. , Henry Carolyn , Papageorgio Chris , Bhattacharyya Kiran , Viator John A.
Published: July 2009

Melanoma is the deadliest form of skin cancer and has the fastest growth rate of all cancer types. Proper staging of melanoma is required for clinical management. One method of staging melanoma is performed by taking a sentinel node biopsy, in which the first node in the lymphatic drainage path of the primary lesion is removed and tested for the presence of melanoma cells. Current standard of care typically involves taking fewer than ten histologic sections of the node out of the hundreds of possible sections available in the tissue. We have developed a photoacoustic method that probes the entire intact node. We acquired a lymph node from a healthy canine subject. We cultured a malignant human melanoma cell line HS 936. Approximately 1×106 cells were separated and injected into the lymph node. We also had a healthy lymph node in which no melanoma cells were implanted. We used a tunable laser system set at 532 nm to irradiate the lymph nodes. Three piezoelectric acoustic detectors were positioned near the lymph node to detect photoacoustic pulses generated within the lymph nodes. We also acquired lymph nodes from pigs and repeated the experiments with increased amplification and improved sensors. We detected photoacoustic responses from a lymph node with as few as 500 melanoma cells injected into the tissue, while normal lymph nodes showed no response. Photoacoustic generation can be used to detect melanoma micrometastasis in sentinel lymph nodes. This detection can be used to guide further histologic study of the node, increasing the accuracy of the sentinel lymph node biopsy.
The influence of external load and air pressure on air slide table performance of ultraprecision machines in nanomachining
Authors: Vahdati Mehrdad , Vahdati Nader
Published: July 2009

In nanomachining, which is a relatively new technology in cutting category, applied device is an ultraprecision machine. In this machine there are two main subassemblies creating rotational and linear motions, air spindle and linear air table, respectively. The linear air table has been simulated experimentally by a linear air bearing. This bearing creates motion in main direction of X and has straightness error motions in Y and Z directions as well. There are also rotational errors around X, Y, and Z axes. The errors are variable according to different parameters. This investigation studies on the rotational errors and deals with the influential parameters and their proportion. As far as the two mating surfaces are separated by a thin layer of pressurized air, the air pressure, the location, and amount of external load are some of the parameters which have been studied. Results show that the more air pressures, the more stable and stiff table is obtainable. Moreover, there will be less error motions. The error amount is not similar in X, Y, or Z direction. Finally the best air pressure and external load and load location have been derived.
Analytical model for ArF photoresist shrinkage under scanning electron microscopy inspection
Authors: Ayal Guy , Andelman David , Cohen Yachin
Published: July 2009

Linewidth slimming is a phenomenon occurring specifically in photolithography of 193 nm wavelength (ArF) radiation. Photoresists for this wavelength appear to lose volume when exposed to electron-beam radiation, as when scanned in scanning electron microscopy for critical dimension (linewidth) measurement. This work is an attempt to understand this “shrinkage” from a polymer physics point of view. More specifically, the authors try to check the applicability of free volume theory in polymer systems by calculating some relevant physical properties, assuming that the exposure to e-beam creates an external hardened shell for the material bulk, and continued exposure will deliver heat into the polymer enclosed in a confined space. The authors’ main conclusion is that the free volume loss (annealing) shows qualitative resemblance to experiment, but this effect exclusively is not a sufficient quantitative explanation for the observed shrinkage. A possible explanation for this discrepancy is that their model is limited due to unknown material parameters, or that the annealing is coupled with other effects such as “wringing” solvent out.
Learning English vowels with different first-language vowel systems II: Auditory training for native Spanish and German speakers
Authors: Iverson Paul , Evans Bronwen G.
Published: July 2009

This study investigated whether individuals with small and large native-language (L1) vowel inventories learn second-language (L2) vowel systems differently, in order to better understand how L1 categories interfere with new vowel learning. Listener groups whose L1 was Spanish (5 vowels) or German (18 vowels) were given five sessions of high-variability auditory training for English vowels, after having been matched to assess their pre-test English vowel identification accuracy. Listeners were tested before and after training in terms of their identification accuracy for English vowels, the assimilation of these vowels into their L1 vowel categories, and their best exemplars for English (i.e., perceptual vowel space map). The results demonstrated that Germans improved more than Spanish speakers, despite the Germans’ more crowded L1 vowel space. A subsequent experiment demonstrated that Spanish listeners were able to improve as much as the German group after an additional ten sessions of training, and that both groups were able to retain this learning. The findings suggest that a larger vowel category inventory may facilitate new learning, and support a hypothesis that auditory training improves identification by making the application of existing categories to L2 phonemes more automatic and efficient.
The sensitivity of auditory-motor representations to subtle changes in auditory feedback while singing
Authors: Keough Dwayne , Jones Jeffery A.
Published: July 2009

Singing requires accurate control of the fundamental frequency (F0) of the voice. This study examined trained singers’ and untrained singers’ (nonsingers’) sensitivity to subtle manipulations in auditory feedback and the subsequent effect on the mapping between F0 feedback and vocal control. Participants produced the consonant-vowel /ta/ while receiving auditory feedback that was shifted up and down in frequency. Results showed that singers and nonsingers compensated to a similar degree when presented with frequency-altered feedback (FAF); however, singers’ F0 values were consistently closer to the intended pitch target. Moreover, singers initiated their compensatory responses when auditory feedback was shifted up or down 6 cents or more, compared to nonsingers who began compensating when feedback was shifted up 26 cents and down 22 cents. Additionally, examination of the first 50 ms of vocalization indicated that participants commenced subsequent vocal utterances, during FAF, near the F0 value on previous shift trials. Interestingly, nonsingers commenced F0 productions below the pitch target and increased their F0 until they matched the note. Thus, singers and nonsingers rely on an internal model to regulate voice F0, but singers’ models appear to be more sensitive in response to subtle discrepancies in auditory feedback.
A model for the perception of environmental sound based on notice-events
Authors: De Coensel Bert , Botteldooren Dick , De Muer Tom , Berglund Birgitta , Nilsson Mats E. , Lercher Peter
Published: July 2009

An approach is proposed to shed light on the mechanisms underlying human perception of environmental sound that intrudes in everyday living. Most research on exposure-effect relationships aims at relating overall effects to overall exposure indicators in an epidemiological fashion, without including available knowledge on the possible underlying mechanisms. Here, it is proposed to start from available knowledge on audition and perception to construct a computational framework for the effect of environmental sound on individuals. Obviously, at the individual level additional mechanisms (inter-sensory, attentional, cognitive, emotional) play a role in the perception of environmental sound. As a first step, current knowledge is made explicit by building a model mimicking some aspects of human auditory perception. This model is grounded in the hypothesis that long-term perception of environmental sound is determined primarily by short notice-events. The applicability of the notice-event model is illustrated by simulating a synthetic population exposed to typical Flemish environmental noise. From these simulation results, it is demonstrated that the notice-event model is able to mimic the differences between the annoyance caused by road traffic noise exposure and railway traffic noise exposure that are also observed empirically in other studies and thus could provide an explanation for these differences.
Patch near field acoustic holography based on particle velocity measurements
Authors: Zhang Yong-Bin , Jacobsen Finn , Bi Chuan-Xing , Chen Xin-Zhao
Published: July 2009

Patch near field acoustic holography (PNAH) based on sound pressure measurements makes it possible to reconstruct the source field near a source by measuring the sound pressure at positions on a surface that is comparable in size to the source region of concern. Particle velocity is an alternative input quantity for NAH, and the advantage of using the normal component of the particle velocity rather than the sound pressure as the input of conventional spatial Fourier transform based NAH and as the input of the statistically optimized variant of NAH has recently been demonstrated. This paper examines the use of particle velocity as the input of PNAH. Because the particle velocity decays faster toward the edges of the measurement aperture than the pressure does and because the wave number ratio that enters into the inverse propagator from pressure to velocity amplifies high spatial frequencies, PNAH based on particle velocity measurements can give better results than the pressure-based PNAH with a reduced number of iterations. A simulation study, as well as an experiment carried out with a pressure-velocity sound intensity probe, demonstrates these findings.
Sensitivity to interaural time difference with bilateral cochlear implants: Development over time and effect of interaural electrode spacing
Authors: Poon Becky B. , Eddington Donald K. , Noel Victor , Colburn H. Steven
Published: July 2009

Sensitivity to interaural time difference (ITD) in constant-amplitude pulse trains was measured in four sequentially implanted bilateral cochlear implant (CI) subjects. The sensitivity measurements were made as a function of time beginning directly after the second ear was implanted, continued for periods of months before subjects began wearing bilateral sound processors, and extended for months while the subjects used bilateral sound processors in day-to-day listening. Measurements were also made as a function of the relative position of the left/right electrodes. The two subjects with the shortest duration of binaural deprivation before implantation demonstrated ITD sensitivity soon after second-ear implantation (before receiving the second sound processor), while the other two did not demonstrate sensitivity until after months of daily experience using bilateral processors. The interaural mismatch in electrode position required to decrease ITD sensitivity by a factor of 2 (half-width) for CI subjects was five times greater than the half-width for interaural carrier-frequency disparity in normal-hearing subjects listening to sinusoidally amplitude-modulated high-frequency tones. This large half-width is likely to contribute to poor binaural performance in CI users, especially in environments with multiple broadband sound sources.
Outer hair cell electromechanical properties in a nonlinear piezoelectric model
Authors: Liu Yi-Wen , Neely Stephen T.
Published: July 2009

A nonlinear piezoelectric circuit is proposed to model electromechanical properties of the outer hair cell (OHC) in mammalian cochleae. The circuit model predicts (a) that the nonlinear capacitance decreases as the stiffness of the load increases, and (b) that the axial compliance of the cell reaches a maximum at the same membrane potential for peak capacitance. The model was also designed to be integrated into macro-mechanical models to simulate cochlear wave propagation. Analytic expressions of the cochlear-partition shunt admittance and the wave propagation function are derived in terms of OHC electro-mechanical parameters. Small-signal analyses indicate that, to achieve cochlear amplification, (1) nonlinear capacitance must be sufficiently high and (2) the OHC receptor current must be sensitive to the velocity of the reticular lamina.
Coherence function for the stochastic scattering by a time-varying, slightly rough, acoustically soft surface
Authors: Scharstein Robert W. , Keiffer Richard S.
Published: July 2009

Approximations for the coherence function of the random acoustic field scattered by a moving rough surface are extracted from a second-order perturbation expansion. The statistically rough surface is characterized by a simple, wide-sense stationary autocorrelation function that exhibits temporal and spatial dispersive behavior in terms of three parameters: the acoustically-small mean-square surface height, a correlation length, and a group velocity. Excitation is provided by the quintessential obliquely-incident time-harmonic plane-wave. Asymptotic evaluation of Fourier integral representations of the stochastic field yields expressions for the coherence function that explicitly display the dependence upon the space and time coordinates and their interaction via the geometrical parameters of the rough surface.
Coherent and incoherent scattering by a plume of particles advected by turbulent velocity flow
Authors: Palmer David R.
Published: July 2009

Studies of acoustic remote sensing of the plumes that result from the injection of particulate matter in the ocean, either naturally or by dumping or dredging activities, have assumed the scattering is incoherent. These plumes are always turbulent, however. The particle density is a passive scalar that is advected by the turbulent velocity flow. The possibility exists, therefore, that the scattered waves from a significant number of particles add coherently as a result of Bragg scattering. In this paper, we investigate this possibility. We derive an expression for the ratio of the coherent intensity to the incoherent one in terms of the turbulent spectrum and the properties of the particles that make up the plume. The sonar is modeled as a high-Q, monostatic, pulsed sonar with arbitrary pulse envelope and arbitrary, but narrow, beam pattern. We apply the formalism to acoustic remote sensing of black smoker hydrothermal plumes. We find that, at most, the coherent intensity is less than 1% of the incoherent one. The implications are that Bragg scattering does not lead to a significant coherent component and in analyses of scattering from this type of plume, one can ignore the complications of turbulence altogether.
Acoustic response of a rigid-frame porous medium plate with a periodic set of inclusions
Authors: Groby J.-P. , Wirgin A. , De Ryck L. , Lauriks W. , Gilbert R. P. , Xu Y. S.
Published: July 2009

The acoustic response of a rigid-frame porous plate with a periodic set of inclusions is investigated by a multipole method. The acoustic properties, in particular, the absorption, of such a structure are then derived and studied. Numerical results together with a modal analysis show that the addition of a periodic set of high-contrast inclusions leads to the excitation of the modes of the plate and to a large increase in the acoustic absorption.
Perceptual contributions of the consonant-vowel boundary to sentence intelligibility
Authors: Fogerty Daniel , Kewley-Port Diane
Published: July 2009

Although research has focused on the perceptual contribution of consonants to spoken syllable or word intelligibility, in sentences vowels have a distinct perceptual advantage over consonants in determining intelligibility [Kewley-Port et al., J. Acoust. Soc. Am. 122, 2365–2375 (2007)]. The current study used a noise replacement paradigm to investigate how perceptual contributions of consonants and vowels are mediated by transitional information at segmental boundaries. The speech signal preserved between replacements is defined as a glimpse window. In the first experiment, glimpse windows contained proportional amounts of transitional boundary information that was either added to consonants or deleted from vowels. Results replicated a two-to-one vowel advantage for intelligibility at the traditional consonant-vowel boundary and suggest that vowel contributions remain robust against proportional deletions of the signal. The second experiment examined the combined effect of random glimpse windows not locked to segments and the distributions of durations measured from the consonant versus vowel glimpses observed in Experiment 1. Results demonstrated that, for random glimpses, the cumulative sentence duration glimpsed was an excellent predictor of performance. Comparisons across experiments confirmed that higher proportions of vowel information within glimpses yielded the highest sentence intelligibility.
Grating lobe reduction in transducer arrays through structural filtering of supercritical plates
Authors: Anderson Brian E. , Hughes W. Jack , Hambric Stephen A.
Published: July 2009

The effect of placing a structural acoustic filter between water and the transducer elements of an array to help reduce undesirable grating lobes is investigated. A supercritical plate is mounted to transducer elements with a thin decoupling polyurethane layer between the transducers and the plate. The plate acts as a radiation/incidence angle filter to pass energy at angles near normal incidence, but suppress energy at large incidence angles. Grating lobe reduction is achieved at the expense of limiting the available steering of the main lobe. Within this steer angle limitation, the main lobe can be steered as normal while the grating lobe level is reduced by the plate’s angular filtering. The insertion of a plate structural filter provides, in principal, an inexpensive and easily implemented approach to extend usable frequency bandwidth with reduced level grating lobes, without increasing the number of array elements. Even though the data match theory well, a practical material has yet to be found that possesses optimal material properties to make the proposed idea practical. This work represents the first attempt to advantageously utilize a plate above its critical frequency to provide angular dependent sound transmission filtering.
Development of a noise metric for assessment of exposure risk to complex noises
Authors: Zhu Xiangdong , Kim Jay H. , Song Won Joon , Murphy William J. , Song Seongho
Published: July 2009

Many noise guidelines currently use A-weighted equivalent sound pressure level LAeq as the noise metric and the equal energy hypothesis to assess the risk of occupational noises. Because of the time-averaging effect involved with the procedure, the current guidelines may significantly underestimate the risk associated with complex noises. This study develops and evaluates several new noise metrics for more accurate assessment of exposure risks to complex and impulsive noises. The analytic wavelet transform was used to obtain time-frequency characteristics of the noise. 6 basic, unique metric forms that reflect the time-frequency characteristics were developed, from which 14 noise metrics were derived. The noise metrics were evaluated utilizing existing animal test data that were obtained by exposing 23 groups of chinchillas to, respectively, different types of noise. Correlations of the metrics with the hearing losses observed in chinchillas were compared and the most promising noise metric was identified.
Identification of the aeroacoustic response of a low Mach number flow through a T-joint
Authors: Martínez-Lera P. , Schram C. , Föller S. , Kaess R. , Polifke W.
Published: July 2009

A methodology to study numerically the aeroacoustic response of low Mach number confined flows to acoustic excitations is presented. The approach combines incompressible flow computations, vortex sound theory, and system identification techniques, and is applied here to study the behavior of a two-dimensional laminar flow through a T-joint. Comparison with experimental results available in literature shows that the computed source models capture the main physical mechanisms of the sound production in the shear layer of the T-joint.
Analysis of the part-pedaling effect in the piano
Authors: Lehtonen Heidi-Maria , Askenfelt Anders , Välimäki Vesa
Published: July 2009

This letter reports basic acoustic phenomena related to part-pedaling in the piano. With part-pedaling, the piano tone can be divided into three distinct time intervals: initial free vibration, damper-string interaction, and final free vibration. Varying the distance of the damper from the string, the acoustic signal and the damper acceleration were measured for several piano tones. During the damper-string interaction, the piano tone decay is rapid and the timbre of the tone is affected by the nonlinear amplitude limitation of the string motion. During the final free decay, the string continues to vibrate freely with a lower decay rate.
Influence of the anisotropy on zero-group velocity Lamb modes
Authors: Prada Claire , Clorennec Dominique , Murray Todd W. , Royer Daniel
Published: July 2009

Guided waves in a free isotropic plate (symmetric Sn and antisymmetric An Lamb modes) exhibit a resonant behavior at frequencies where their group velocity vanishes while their phase velocity remains finite. Previous studies of this phenomenon were limited to isotropic materials. In this paper, the optical generation and detection of these zero-group velocity (ZGV) Lamb modes in an anisotropic plate is investigated. With a circular laser source, multiple local resonances were observed on a silicon wafer. Experiments performed with a line source demonstrated that the frequency and the amplitude of these resonances depend on the line orientation. A comparison between experimental and theoretical dispersion curves for waves propagating along the [100] and [110] directions of the silicon crystal verified that these resonances occur at the minimum frequency of the S1 and A2 Lamb modes. Simulations indicated that it is possible to deduce the three elastic constants of the plate material with good accuracy from these measurements.
In Vitro Activity and In Vivo Efficacy of Clavulanic Acid against
Acinetobacter baumannii
Authors: Beceiro Alejandro , López-Rojas Rafael , Domínguez-Herrera Juan , Docobo-Pérez Fernando , Bou Germán , Pachón Jerónimo
Published: July 2009

Clavulanic acid (CLA) exhibits low MICs against some
Acinetobacter baumannii
strains. The present study evaluates the efficacy of CLA in a murine model of
A. baumannii
pneumonia. For this purpose, two clinical strains, Ab11 and Ab51, were used; CLA MICs for these strains were 2 and 4 mg/liter, respectively, and the imipenem (IPM) MIC was 0.5 mg/liter for both. A pneumonia model in C57BL/6 mice was used. The CLA dosage (13 mg/kg of body weight given intraperitoneally) was chosen to reach a maximum concentration of the drug in serum similar to that in humans and a time during which the serum CLA concentration remained above the MIC equivalent to 40% of the interval between doses. Six groups (
n
= 15) were inoculated with Ab11 or Ab51 and were allocated to IPM or CLA therapy or to the untreated control group. In time-kill experiments, CLA was bactericidal only against Ab11 whereas IPM was bactericidal against both strains. CLA and IPM both decreased bacterial concentrations in lungs, 1.78 and 2.47 log
10
CFU/g (
P
≤ 0.001), respectively, in the experiments with Ab11 and 2.42 and 2.28 log
10
CFU/g (
P
≤ 0.001), respectively, with Ab51. IPM significantly increased the sterility of blood cultures over that for the controls with both strains (
P
≤ 0.005); CLA had the same effect with Ab51 (
P
< 0.005) but not with Ab11 (
P
= 0.07). For the first time, we suggest that CLA may be used for the treatment of experimental severe
A. baumannii
infections.
Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission
Authors: Georges Bernard , Conil Jean-Marie , Seguin Thierry , Ruiz Stéphanie , Minville Vincent , Cougot Pierre , Decun Jean-François , Gonzalez Hélène , Houin Georges , Fourcade Olivier , Saivin Sylvie
Published: July 2009

The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.
Species Identification and Antifungal Susceptibility Patterns of Species Belonging to
Aspergillus
Section
Nigri
Authors: Alcazar-Fuoli Laura , Mellado Emilia , Alastruey-Izquierdo Ana , Cuenca-Estrella Manuel , Rodriguez-Tudela Juan L.
Published: July 2009

A phylogenetic analysis was performed for 34
Aspergillus
strains belonging to section
Nigri
. Molecular methods allowed for the correct classification into three different clades (
A. niger
,
A. tubingensis
, and
A. foetidus
). Correlation with in vitro itraconazole susceptibility distinguished the following three profiles: susceptible, resistant, and showing a paradoxical effect. A number of different species whose morphological features resemble those of
A. niger
showed unusual MICs to itraconazole that have never been described for the
Aspergillus
genus.
Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?
Authors: Hirt Déborah , Urien Saik , Olivier Mathieu , Peyrière Hélène , Nacro Boubacar , Diagbouga Serge , Zoure Emmanuelle , Rouet François , Hien Hervé , Msellati Philippe , Van De Perre Philippe , Tréluyer Jean-Marc
Published: July 2009

We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (CminandCmax, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The thresholdCmin(and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) hadCmins below 1 mg/liter. A significantly higher percentage of children withCmins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children withCmins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.
Novel Broad-Spectrum Bis-(Imidazolinylindole) Derivatives with Potent Antibacterial Activities against Antibiotic-Resistant Strains
Authors: Panchal Rekha G. , Ulrich Ricky L. , Lane Douglas , Butler Michelle M. , Houseweart Chad , Opperman Timothy , Williams John D. , Peet Norton P. , Moir Donald T. , Nguyen Tam , Gussio Rick , Bowlin Terry , Bavari Sina
Published: July 2009

Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeutics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following infection with
Bacillus anthracis
, a gram-positive spore-forming bacterium. Four bis-(imidazolinylindole) compounds were identified with potent antibacterial activity as measured by the protection of macrophages and by the inhibition of bacterial growth in vitro. These compounds were effective against a broad range of gram-positive and gram-negative bacterial species, including several antibiotic-resistant strains. Minor structural variations among the four compounds correlated with differences in their effects on bacterial macromolecular synthesis and mechanisms of resistance. In vivo studies revealed protection by two of the compounds of mice lethally infected with
B. anthracis
,
Staphylococcus aureus
, or
Yersinia pestis
. Taken together, these results indicate that the bis-(imidazolinylindole) compounds represent a new chemotype for the development of therapeutics for both gram-positive and gram-negative bacterial species as well as against antibiotic-resistant infections.
Virulence and Cellular Interactions ofBurkholderia multivoransin Chronic Granulomatous Disease
Authors: Zelazny Adrian M. , Ding Li , Elloumi Houda Z. , Brinster Lauren R. , Benedetti Fran , Czapiga Meggan , Ulrich Ricky L. , Ballentine Samuel J. , Goldberg Joanna B. , Sampaio Elizabeth P. , Holland Steven M.
Published: July 2009

Chronic granulomatous disease (CGD) patients are susceptible to life-threatening infections by theBurkholderia cepaciacomplex. We used leukocytes from CGD and healthy donors and compared cell association, invasion, and cytokine induction byBurkholderia multivoransstrains. A CGD isolate, CGD1, showed higher cell association than that of an environmental isolate, Env1, which correlated with cell entry. AllB. multivoransstrains associated significantly more with cells from CGD patients than with those from healthy donors. Similar findings were observed with another CGD pathogen,Serratia marcescens, but not withEscherichia coli. In a mouse model of CGD, strain CGD1 was virulent while Env1 was avirulent.B. multivoransorganisms were found in the spleens of CGD1-infected mice at levels that were 1,000 times higher than those found in Env1-infected mice, which was coincident with higher levels of the proinflammatory cytokine interleukin-1β. Taken together, these results may shed light on the unique susceptibility of CGD patients to specific pathogens.
Community-Wide Response of the Gut Microbiota to Enteropathogenic
Citrobacter rodentium
Infection Revealed by Deep Sequencing
Authors: Hoffmann Christian , Hill David A. , Minkah Nana , Kirn Thomas , Troy Amy , Artis David , Bushman Frederic
Published: July 2009

We investigated the spatial and temporal response of the murine gut microbiome to infection with
Citrobacter rodentium
, an attaching-and-effacing bacterium that provokes innate and adaptive immune responses, resulting in transient bacterial colitis. Previous studies have suggested that
C. rodentium
-induced inflammation is associated with an increased abundance of
Enterobacteriaceae
. We report here a deeper analysis of this model using DNA bar coding and 454 pyrosequencing to characterize 101,894 partial 16S rRNA gene sequences from 85 microbial samples from tissue-adhered and luminal bacteria of the cecum, proximal colon, and distal colon, which allowed us to identify previously unappreciated spatial and kinetic changes in multiple bacterial lineages. The deep sequencing data revealed that
C. rodentium
was most abundantly associated with the cecal mucosa at day 9 postinfection and then diminished in abundance, providing the first reported use of deep sequencing to track a pathogen in vivo through the course of infection. Notable changes were associated with both the mucosally adhered and luminal microbiota at both day 9 and day 14 postinfection. Alterations in abundance were seen for
Proteobacteria, Deferribacteres, Clostridia
, and others; however, changes in
Enterobacteriaceae
could be accounted for by the presence of
C. rodentium
itself, which is a member of this family. The
Lactobacillus
group decreased in abundance during infection, which may be important for pathogenesis because members of this lineage modulate the composition of the gut microbiota and are used as probiotics. Thus, deep sequencing provides previously inaccessible information on how
Citrobacter
infection and clearance reshapes the gut microbial community in space and time.
Characterization of the Effects of Salicylidene Acylhydrazide Compounds on Type III Secretion in
Escherichia coli
O157:H7
Authors: Tree Jai J. , Wang Dai , McInally Carol , Mahajan Arvind , Layton Abigail , Houghton Irene , Elofsson Mikael , Stevens Mark P. , Gally David L. , Roe Andrew J.
Published: July 2009

Recent work has highlighted a number of compounds that target bacterial virulence by affecting gene regulation. In this work, we show that small-molecule inhibitors affect the expression of the type III secretion system (T3SS) of
Escherichia coli
O157:H7 in liquid culture and when this bacterium is attached to bovine epithelial cells. Inhibition of T3SS expression resulted in a reduction in the capacity of the bacteria to form attaching and effacing lesions. Our results show that there is marked variation in the abilities of four structurally related compounds to inhibit the T3SS of a panel of isolates. Using transcriptomics, we performed a comprehensive analysis of the conserved and inhibitor-specific transcriptional responses to these four compounds. These analyses of gene expression show that numerous virulence genes, located on horizontally acquired DNA elements, are affected by the compounds, but the number of genes significantly affected varied markedly for the different compounds. Overall, we highlight the importance of assessing the effect of such “antivirulence” agents on a range of isolates and discuss the possible mechanisms which may lead to the coordinate downregulation of horizontally acquired virulence genes.
Cryptococcus gattiiIsolates from the British Columbia Cryptococcosis Outbreak Induce Less Protective Inflammation in a Murine Model of Infection thanCryptococcus neoformans
Authors: Cheng Po-Yan , Sham Anita , Kronstad James W.
Published: July 2009

The fungal pathogenCryptococcus neoformanscauses approximately one million cases of cryptococcosis per year in people with AIDS. In contrast, the related speciesC. gattiiis responsible for a much smaller number of cases, but these often occur in immunocompetent people. In fact,C. gattiihas emerged in the last decade as the frequent cause of cryptococcosis in otherwise healthy people in British Columbia. We analyzed the immune responses elicited by threeC. gattiistrains and oneC. neoformansstrain in mice as a first step toward understanding whyC. gattiiis able to cause disease in immunocompetent hosts. TheC. gattiistrains all induced a less protective inflammatory response in C57BL/6 mice by inhibiting or failing to provoke the migration of neutrophils to sites of infection. TheC. gattiistrains also failed to elicit the production of protective cytokines, such as tumor necrosis factor alpha, compared to the ability of theC. neoformansstrain. Despite these differences, the strain representing the major outbreak genotype from British Columbia showed a virulence equivalent to that of theC. neoformansstrain, while two otherC. gattiistrains had reduced virulence. Taken together, our results indicate thatC. gattiistrains thrive in immunocompetent hosts by evading or suppressing the protective immune responses that normally limit the progression of disease caused byC. neoformans.
Vaccination with an Attenuated Strain of
Francisella novicida
Prevents T-Cell Depletion and Protects Mice Infected with the Wild-Type Strain from Severe Sepsis
Authors: Sharma Jyotika , Li Qun , Mishra Bibhuti B. , Georges Michelle J. , Teale Judy M.
Published: July 2009

Francisella tularensis
is the causative agent of zoonotic tularemia, a severe pneumonia in humans, and
Francisella novicida
causes a similarly severe tularemia in mice upon inhalation. The correlates of protective immunity, as well as the virulence mechanisms of this deadly pathogen, are not well understood. In the present study, we compared the host immune responses of lethally infected and vaccinated mice to highlight the host determinants of protection from this disease. Intranasal infection with an attenuated mutant (Mut) of
F. novicida
lacking a 58-kDa hypothetical protein protected C57BL/6 mice from a subsequent challenge with the fully virulent wild-type strain U112 via the same route. The protection conferred by Mut vaccination was associated with reduced bacterial burdens in systemic organs, as well as the absence of bacteremia. Also, there was reduced lung pathology and associated cell death in the lungs of vaccinated mice. Both vaccinated and nonvaccinated mice displayed an initial 2-day delay in upregulation of signature inflammatory mediators after challenge. Whereas the nonvaccinated mice developed severe sepsis characterized by hypercytokinemia and T-cell depletion, the vaccinated mice displayed moderated cytokine induction and contained increased numbers of αβ T cells. The recall response in vaccinated mice consisted of a characteristic Th1-type response in terms of cytokines, as well as antibody isotypes. Our results show that a regulated Th1 type of cell-mediated and humoral immunity in the absence of severe sepsis is associated with protection from respiratory tularemia, whereas a deregulated host response leading to severe sepsis contributes to mortality.
Important Science—It's All about the SPIN
Authors: Casadevall Arturo , Fang Ferric C.
Published: July 2009

The importance of a scientific finding can be difficult to ascertain because it requires both subjective judgment and foresight. We propose criteria, based upon whether a discovery is sizeable (S), practical (P), integrated (I), and new (N), that can be used individually or collectively to systematically assess the importance of a finding.
Antigen Display, T-Cell Activation, and Immune Evasion during Acute and Chronic Ehrlichiosis
Authors: Nandi Bisweswar , Chatterjee Madhumouli , Hogle Kathryn , McLaughlin Maura , MacNamara Katherine , Racine Rachael , Winslow Gary M.
Published: July 2009

How spatial and temporal changes in major histocompatibility complex/peptide antigen presentation to CD4 T cells regulate CD4 T-cell responses during intracellular bacterial infections is relatively unexplored. We have shown that immunization with an ehrlichial outer membrane protein, OMP-19, protects mice against fatal ehrlichial challenge infection, and we identified a CD4 T-cell epitope (IAb/OMP-19107-122) that elicited CD4 T cells following either immunization or infection. Here, we have used an IAb/OMP-19107-122-specific T-cell line to monitor antigen display ex vivo during acute and chronic infection withEhrlichia muris, a bacterium that establishes persistent infection in C57BL/6 mice. The display of IAb/OMP-19107-122by host antigen-presenting cells was detected by measuring intracellular gamma interferon (IFN-γ) production by the T-cell line. After intravenous infection, antigen presentation was detected in the spleen, peritoneal exudate cells, and lymph nodes, although the kinetics of antigen display differed among the tissues. Antigen presentation and bacterial colonization were closely linked in each anatomical location, and there was a direct relationship between antigen display and CD4 T-cell effector function. Spleen and lymph node dendritic cells (DCs) were efficient presenters of IAb/OMP-19107-122, demonstrating that DCs play an important role in ehrlichial infection and immunity. Chronic infection and antigen presentation occurred within the peritoneal cavity, even in the presence of highly activated CD4 T cells. These data indicated that the ehrlichiae maintain chronic infection not by inhibiting antigen presentation or T-cell activation but, in part, by avoiding signals mediated by activated T cells.
Physical activity, cardiorespiratory fitness and the incidence of type 2 diabetes in a prospective study of men
Authors: Sieverdes John C , Sui Xuemei , Lee Duck-chul , Church Timothy S , McClain Amanda , Hand Gregory A , Blair Steven N
Published: July 2009

Objective

To assess the independent and joint associations between self-reported physical activity (PA) and objectively measured cardiorespiratory fitness (CRF) from a maximal treadmill exercise test and the development of type 2 diabetes mellitus in a large cohort of men.

Methods

Participants for the current analysis were 23 444 men aged 20–85 years free of cardiovascular disease (CVD), cancer or diabetes at baseline. Incident diabetes were identified from mail-back surveys. Cox regression analysis was used to estimate hazard ratios (HRs), 95% confidence intervals (CIs) and diabetes incidence rates (per 10 000 man-years) according to exposure categories.

Results

During an average of 18 years of follow-up, 589 incident cases of diabetes were identified. After adjusting for age, examination year, survey response pattern, body mass index, smoking, drinking, fasting glucose, chronic diseases and family history of CVD or diabetes, the walking/jogging/running (WJR) and sport/fitness groups had a 40% and 28% lower risk of developing diabetes compared with the sedentary men, respectively (both p < 0.05). For CRF, diabetes incidence rates were 31.9, 14.5 and 6.5 for low-, moderate- and high-fitness groups, respectively. After adjustment for the above covariables, moderate and high CRF had a 38% and 63% lower risk of developing diabetes compared with the low CRF group (p trend<0.0001).

Conclusion

Our findings showed a lower risk of developing diabetes for men who participated in a WJR programme or sport/fitness activity, compared with those who were sedentary. Higher levels of fitness were associated with an inverse gradient of incident diabetes.