bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictions of magnetosheath merging between IMF field lines of opposite polarity
Authors: Maynard N. C. , Sonnerup B. U. Ö. , Siscoe G. L. , Weimer D. R. , Siebert K. D. , Erickson G. M. , White W. W. , Schoendorf J. A. , Ober D. M. , Wilson G. R. , Heinemann M. A.
Published: December 2002

Magnetohydrodynamic (MHD) simulations using the Integrated Space Weather Prediction Model (ISM) show merging in the magnetosheath between interplanetary magnetic field (IMF) field lines on opposite sides of a directional discontinuity. As the discontinuity passes the bow shock and traverses the magnetosheath, the magnetic field gradients on either side become steeper, and the geometry is distorted by the nonuniform flow speed in the magnetosheath. Associated current densities are intensified. In a location isolated from the magnetopause, we use the appearance of an X magnetic field configuration, associated dissipation electric fields, and increases in plasma velocity in the exhaust direction from the X as evidence for merging in the magnetosheath. We suggest that these signatures might be observable by Polar, as it now traverses the magnetosheath near the nose or by the Cluster spacecraft when the discontinuity is tilted away from the YZ plane. Merging signatures are seen in simulations with both 90° and 180° rotations of the field across the discontinuity. Magnetosheath merging creates a hole in the directional discontinuity, allowing the magnetosphere to penetrate through the structure as the discontinuity passes downstream. Magnetosheath merging has the potential to affect ionospheric convection pattern changes, open–closed boundaries, and magnetotail dynamics. A possible association with hot flow anomalies (HFA) is also indicated.
IMAGE/high‐energy energetic neutral atom: Global energetic neutral atom imaging of the plasma sheet and ring current during substorms
Authors: C:son Brandt P. , Demajistre R. , Roelof E. C. , Ohtani S. , Mitchell D. G. , Mende S.
Published: December 2002

Energetic neutral atom (ENA) images in the 10–60 keV range show the substorm dynamics of the ion distribution out to 14 RE in the plasma sheet. The images were obtained during two substorms in the mainphase of the 4 October 2000 storm by the high‐energy energetic neutral atom (HENA) imager on board the IMAGE satellite. During the two substorm sequences the edge of the most tailward ENA emissions appears to move earthward in association with dipolarization observed at geosynchronous distance by the GOES satellite. At the time of geosynchronous dipolarization, the auroral onset was observed by the far ultra violet (FUV) imager onboard IMAGE. Preliminary equatorial ion distributions derived from the individual ENA images in the substorm sequences have been obtained through a constrained linear inversion technique. The results show that the ion fluxes in the >8 RE plasma sheet suddenly decrease around dipolarization during approximately 30 min. About 12–20 min after the start of the plasma sheet flux decrease, ion injections are seen by the geosynchronous satellites. The peak of the ring current flux is pushed in from geosynchronous to L = 4 over the substorm sequences. Two exospheric models are used in the inversion. We find that more realistic plasma sheet fluxes are obtained with an exospheric model that contains enhanced exospheric hydrogen densities on the nightside. Implications for earthward propagation of the plasma sheet ion distribution during dipolarization are discussed.
Plasma structures of 3‐meter type 1 and type 2 irregularities in nighttime midlatitude sporadic E region
Authors: Chu Yen‐Hsyang , Wang Chien‐Ya
Published: December 2002

Although the plausible mechanisms involved in the generation of midlatitude type 1 sporadic E (Es) irregularities have been suggested, rare observational evidence is provided to validate the proposed plasma structure associated with the midlatitude type 1 Es irregularities. In this article, the type 1 echoes observed by the Chung‐Li VHF radar located in the equatorial anomalous region are interferometrically analyzed and the corresponding plasma structure of the type 1 irregularities is reconstructed. We find that the plasma structure has sharp lateral and top and bottom boundaries with thickness of about 1–2 km and horizontal extent of about 3–5 km in E‐W direction. Its dimension in N‐S direction cannot be resolved by using interferometry technique because of considerably narrow width of expected echoing region in elevation. The observed Doppler velocity of the type 1 echoes can be as low as 220 m/s, substantially smaller than nominal ion acoustic wave speed (about 360 m/s) in Es region. The spatial structure of the concurrent type 2 irregularities is also reconstructed. The result strongly suggests that it be a well‐defined thin layer with thickness of 1–2 km and horizontal extent of 9–17 km in E‐W direction, very different from that of the type 1 irregularities. The whole structure of type 1 irregularities moves bodily toward east at speed of about 31 m/s, and no vertical displacement of the structure is observed. Although the movement of the layer structure of the type 2 irregularities in E‐W direction is indistinct, it descends remarkably at a rate of 10.3 m/s. These features imply that for the present case the factors governing the dynamic behavior of the type 1 and type 2 irregularities are different and independent, irrespective of the fact that the clump of the type 1 irregularities separates from that of concurrent type 2 irregularities only by about 4 km in distance.
Proton core temperature effects on the relative drift and anisotropy evolution of the ion beam instability in the fast solar wind
Authors: Araneda Jaime A. , Viñas Adolfo F. , Astudillo Hernán F.
Published: December 2002

Typical nonthermal features of ion velocity distributions observed in the fast solar wind are the relative streaming between two proton components, an alpha/proton relative flow, and anisotropic proton cores with T⟂p > T∥p, where the subscripts denote directions relative to the background magnetic field B0. All these nonthermal features lead to the growth of the several electromagnetic instabilities. Here, linear Vlasov theory and one‐dimensional hybrid simulations are used to study these instabilities in a homogeneous, magnetized, and collisionless plasma model. Under these conditions, both magnetosonic and Alfvén/cyclotron modes become unstable. We show that for conditions typical of the fast solar wind and parallel propagation, the proton core temperature anisotropy plays a significant role in modifying the wave‐particle scattering of each ion component as compared to the isotropic case. Such an effect leads to a reduction in both the heating and anisotropy enhancement of the proton beam and alpha component and to a decrease in the relative proton/proton and proton/alpha flow speeds below the corresponding isotropic instability thresholds. This result provides additional support to the physical scenario in which instability thresholds correspond to observable constraints on plasma species anisotropies and match closer recent solar wind observations.
Traveling convection vortices induced by solar wind tangential discontinuities
Authors: Kataoka R. , Fukunishi H. , Lanzerotti L. J. , Rosenberg T. J. , Weatherwax A. T. , Engebretson M. J. , Watermann J.
Published: December 2002

Two typical magnetic impulse events (MIEs) accompanied by traveling convection vortices (TCVs) are investigated. The analysis of their conjugate equivalent convection patterns is performed using magnetic field data obtained from high‐latitude ground magnetometer networks in the Northern and Southern Hemispheres. A three‐dimensional analysis of solar wind structures is also performed using solar wind data obtained from multiple International Solar‐Terrestrial Physics satellites. In the first event observed at ∼1310 UT on 22 May 1996, a westward moving TCV appeared simultaneously in the noon‐to‐dawn sector in the Northern and Southern Hemispheres. The solar wind source of this TCV is found to be a tangential discontinuity (TD), which causes a rapid northward turning of the interplanetary magnetic field (IMF) and abrupt dynamic pressure changes. In the second event observed at ∼1610 UT on 27 May 1998, an eastward moving TCV appeared in the noon sector in the Northern and Southern Hemispheres, with a timing delay of 2 to 3 min in the Southern Hemisphere. The solar wind source of this TCV is found again to be a TD, which causes a rapid IMF By negative turning and an abrupt enhancement of dynamic pressure. Analyses show that the TDs driving these events have their motional electric fields pointing toward the TDs and their normal vectors with large cone angles from the sunward direction. These TDs satisfy the conditions for the formation of a hot flow anomaly (HFA) at the bow shock. The sweeping motion across the magnetosphere of the intersection of the TD and the bow shock is found to be consistent with the observed TCV motion in each event. Magnetopause deformations due to HFAs can explain all the observed morphological features and the triggering process of these two MIEs. It is suggested, however, that bursty merging and/or pressure pulses would reinforce the processes produced by the HFAs, since the TDs are usually accompanied by both abrupt IMF changes and pressure enhancements. Consequently, it seems reasonable to conclude that the integrated processes of HFA, bursty magnetic field merging, and pressure pulses produce the evolution of these MIEs and TCVs.
Matchsticks on parade: Vertical axis rotation in oblique divergence
Authors: Markley Michelle J. , Tikoff Basil
Published: December 2002

Our physical experiments investigate vertical axis rotation of long rigid blocks of continental crust during oblique divergence. Experiments use matchsticks embedded in a 2‐cm‐thick layer of silicone gel that overlies a rubber sheet. A new device uses two motors to create oblique divergence, resulting in transtensional deformation in the rubber sheet and silicone gel. During experiments, single matchsticks behave like material lines because they rotate into parallelism with the direction of oblique divergence. Matchsticks in arrays, however, rotate away from parallelism with this direction. The sense and rate of rotation of these matchsticks in arrays depend on the geometry of the array, the scaling of experiments (using the Argand number), and the spacing of the matchsticks. Strain incompatibility between the rigid matchsticks and the deformable silicone builds relief on the surface of experiments. Gravity‐driven flow of silicone away from zones of positive relief causes instability in the orientation of matchsticks in arrays. These dynamic instabilities are consistent with the predictions by Lamb [1994]. Our results have two tectonic implications. First, long, continental crustal blocks may not rotate into parallelism with the direction of oblique divergence. Second, rigid rotation of crustal blocks may create dynamic topography in the rheological layers of the Earth.
Effects of Asian air pollution transport and photochemistry on carbon monoxide variability and ozone production in subtropical coastal south China
Authors: Chan C. Y. , Chan L. Y. , Lam K. S. , Li Y. S. , Harris J. M. , Oltmans S. J.
Published: December 2002

Surface ozone and carbon monoxide (CO) measured from a relatively remote coastal station in Hong Kong are analyzed to study the effects of pollutant transport and associated ozone production on CO and ozone variations in the subtropical south China region. CO and ozone concentrations show a common minimum in summer and in the maritime air masses from the South China Sea and Pacific Ocean. They have higher values in other seasons and in the continental air masses that have passed over mainland Asia and the East Asian coast. CO shows the maximum monthly median of 457–552 ppbv in winter while ozone shows a maximum of 40–50 ppbv in autumn and a distinct peak of 41–43 ppbv in spring. The CO concentrations especially in the continental air masses (median of 277 to 428 ppbv) are very high when compared with measurements in most parts of the world. This suggests that the south China region is under the strong influence of pollutant transport from the Asian continent and East Asian coast. Ozone and CO show strong positive correlations in the polluted maritime air masses and from late spring to early autumn (May–September) with the linear regression slopes of the ozone‐CO plot from 0.08 to 0.22 (with respective standard errors from 0.01 to 0.03). The strong correlations and slopes plus the high CO levels indicate that there is substantial ozone production from pollution in the polluted maritime air masses and in the late spring to early autumn period.
Dynamical response to the solar cycle
Authors: Kodera Kunihiko , Kuroda Yuhji
Published: December 2002

The dynamical impact of the 11‐year solar cycle is investigated with the focus on the stratopause region where solar ultraviolet heating is greatest. The most important variation in solar forcing longer than the diurnal cycle is the annual cycle. Thus the climatological features of the zonal wind variation associated with the annual cycle were first studied to characterize the basic features of the atmosphere's dynamical response to changes in solar radiative forcing. The 11‐year solar cycle effect was then investigated. The results of the analysis suggest that in a climatological mean state the stratopause circulation evolves from a radiatively controlled state to one dynamically controlled during winter in both hemispheres. The transition period is characterized by a poleward shift of the westerly jet. The solar cycle effect appears as a change in the balance between the radiatively and dynamically controlled states. The radiatively controlled state lasts longer during the solar maximum phase, and the stratopause subtropical jet reaches a higher speed. The large dynamical response to relatively weak radiative forcing may be understood by the bimodal nature of the winter atmosphere due to interaction with meridionaly propagating planetary waves and zonal mean zonal winds. It is suggested that the solar influence produced in the upper stratosphere and stratopause region is transmitted to the lower stratosphere through (1) modulation of the internal mode of variation in the polar night jet and (2) a change in the Brewer‐Dobson circulation. The first process is significant in the middle and high latitudes, whereas the latter is prominent in the equatorial region.
Determination of the vertical flux of dimethyl sulfide by eddy correlation and atmospheric pressure ionization mass spectrometry (APIMS)
Authors: Bandy Alan R. , Thornton Donald C. , Tu Fang H. , Blomquist Byron W. , Nadler Wolfgang , Mitchell Glenn M. , Lenschow Donald H.
Published: December 2002

An atmospheric pressure ionization mass spectrometer (APIMS) was developed to determine atmospheric dimethyl sulfide (DMS) with a frequency high enough (25 Hz) to compute vertical fluxes in the marine boundary by eddy correlation. High precision and immunity to sample loss, fluctuations in instrument sensitivity, etc., were achieved by adding isotopically labeled DMS (d3 or d6) continuously to the manifold as an internal standard. Because mixing ratios are determined and not mass concentration, the vertical fluxes obtained did not suffer from “Webb effect” errors. High sensitivity at high humidities was achieved by efficient drying and by preheating the sampled air to about 400 °C. During the National Science Foundation (NSF) Dynamics and Chemistry of Marine Stratocumulus Phase II: Entrainment Studies (DYCOMS II) and Passing Efficiency of the Low Turbulence Inlet (PELTI) programs, DMS and d3‐DMS (or d6‐DMS) were each determined with integration times of 20 ms. From these data the ambient DMS level was computed every 40 ms. Vertical fluxes were determined with a relative precision better than 13%.
Number size distributions and concentrations of marine aerosols: Observations during a cruise between the English Channel and the coast of Antarctica
Authors: Koponen Ismo K. , Virkkula Aki , Hillamo Risto , Kerminen Veli‐Matti , Kulmala Markku
Published: December 2002

Submicron aerosol number size distributions were measured on board the research ship Akademic Fedorov during a cruise from the English Channel to the coast of Antarctica. The observed sized spectra were fitted with three lognormal modes (the nucleation, Aitken and accumulation modes), and the data were classified according to calculated air mass back trajectories. The total particle number concentrations were mostly <1000 cm−3 in marine air masses and between about 1000 and 10000 cm−3 in continentally influenced air masses. Most of the eastern midlatitude Atlantic was affected by European pollution with high concentrations of both nucleation and Aitken mode particles. Another pollution peak, caused probably by biomass burning in Africa, was seen at about 10 N. Marine air masses showed distinctive latitudinal changes. Over the tropical Atlantic no nucleation mode could be seen, and the total particle number concentration remained usually below 500 cm−3. In the midlatitude and high‐latitude Atlantic several episodes of elevated particle concentrations (<1000 cm−3) caused by either the nucleation or Aitken mode were observed. The geometric mean diameter of the accumulation mode decreased gradually toward the higher southern latitudes with a more rapid decline close to Antarctica. Our observations indicate further that there is no simple and universal relationship between the total particle number concentration, the submicron aerosol volume (or mass), and the number of particles able to act as cloud condensation nuclei over the southern hemispheric oceans.
Elevations of water‐worn features on Mars: Implications for circulation of groundwater
Authors: Carr Michael H.
Published: December 2002

Central to the model of the evolution of the martian hydrosphere byClifford and Parker[2001]is a permanent freezing of the planet at the end of the Noachian and recharge of the global groundwater system by basal melting of ice‐rich polar deposits. Acquisition of MOLA data by Mars Global Surveyor provides a means of testing the model, since discharge of water onto the surface, after development of the cryosphere, is driven by the hydrostatic head created by the difference in elevation between the base of the polar‐layered terrain and the discharge site. The new data show that, while most post‐Noachian water‐worn features are at a lower elevation than the base of the polar‐layered terrains, as required by the model, there are exceptions. Prominent among these are possible lacustrine deposits within the canyons, tributaries to the canyons, and valleys on several volcanoes. These high‐standing features can be reconciled with the model if volcanic melting of ice within the cryosphere is invoked as a source for water at high elevations. An alternative is that high pressures may have developed below the cryosphere as a result of water being trapped beneath the growing cryosphere and the impermeable basement. Yet another alternative is that, since the end of the Noachian, the groundwater system has been recharged by precipitation during occasional warm periods.
Huygen's principle applied to radio wave propagation
Authors: Coleman C. J.
Published: December 2002

Huygen's principle, in the form of boundary integral equations, is applied to the problem of radio wave propagation. Complex propagation is analyzed by dividing the region between transmitter and receiver into a number of zones and propagating the solution between these zones by means of integral equations with simple approximate kernels. In the limit that the regions become dense, the approach leads to a useful form of the WKB solution, and this is demonstrated through its application to the study of propagation through a disturbed ionosphere.
Two‐site modeling of rainfall based on the Neyman‐Scott process
Authors: Favre A.‐C. , Musy A. , Morgenthaler S.
Published: December 2002

On the basis of the Neyman‐Scott process a model is proposed to generate rainfall at two sites simultaneously. This model takes into account the correlation, which is produced by generating bivariate correlated variates. The cross correlation between the sites has been computed in order to estimate the parameters. Finally, the model is validated for three pairs of stations situated in the Swiss Plateau region.
In Vitro Drug Interaction Modeling of Combinations of Azoles with Terbinafine against ClinicalScedosporium prolificansIsolates
Authors: Meletiadis Joseph , Mouton Johan W. , Meis Jacques F. G. M. , Verweij Paul E.
Published: December 2002

The in vitro interaction between terbinafine and the azoles voriconazole, miconazole, and itraconazole against five clinicalScedosporium prolificansisolates after 48 and 72 h of incubation was tested by a microdilution checkerboard (eight-by-twelve) technique. The antifungal effects of the drugs alone and in combination on the fungal biomass as well as on the metabolic activity of fungi were measured using a spectrophotometric method and two colorimetric methods, based on the lowest drug concentrations showed 75 and 50% growth inhibition (MIC-1 and MIC-2, respectively). The nature and the intensity of the interactions were assessed using a nonparametric approach (fractional inhibitory concentration [FIC] index model) and a fully parametric response surface approach (Greco model) of the Loewe additivity (LA) no-interaction theory as well as a nonparametric (Prichard model) and a semiparametric response surface approaches of the Bliss independence (BI) no-interaction theory. Statistically significant synergy was found between each of the three azoles and terbinafine in all cases, although with different intensities. A 27- to 64-fold and 16- to 90-fold reduction of the geometric mean of the azole and terbinafine MICs, respectively, was observed when they were combined, resulting in FIC indices of <1 to 0.02. Using the MIC-1 higher levels of synergy were obtained, , which were more consistent between the two incubation periods than using the MIC-2. The strongest synergy among the azoles was found with miconazole using the BI-based models and with voriconazole using the LA-based models. The synergistic effects both on fungal growth and metabolic activity were more potent after 72 h of incubation. Fully parametric approaches in combination with the modified colorimetric method might prove useful for testing the in vitro interaction of antifungal drugs against filamentous fungi.
Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients
Authors: Goujard Cecile , Vincent Isabelle , Meynard Jean-Luc , Choudet Nathalie , Bollens Diane , Rousseau Cyril , Demarles Didier , Gillotin Catherine , Bidault Roselyne , Taburet Anne-Marie
Published: December 2002

The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (
C
min,ss
) was 1.92 μg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 μg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (
C
max,ss
) was 7.12 μg/ml, the area under the concentration-time curve from 0 to 10 h (AUC
0-10
) was 32.06 μg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUC
ss
) was 35.74 μg · h/ml. Decreases in the mean values of
C
min,ss
(29%),
C
max,ss
(42%), AUC
0-10
(42%), and AUC
ss
(40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir
C
min,ss
markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir
C
min,ss
above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.
Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398
Authors: Pfister Marc , Labbé Line , Hammer Scott M. , Mellors John , Bennett Kara K. , Rosenkranz Susan , Sheiner Lewis B.
Published: December 2002

The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (
P
= 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/
F
) of EFV is associated with a greater percent increase in the hazard of virological failure (
P
< 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/
F
.
Modeling of Transfer Kinetics at the Serum-Cerebrospinal Fluid Barrier in Rabbits with Experimental Meningitis: Application to Grepafloxacin
Authors: Pfister Marc , Zhang Liping , Hammarlund-Udenaes Margareta , Sheiner Lewis B. , Gerber Cynthia M. , Täuber Martin G. , Cottagnoud Philippe
Published: December 2002

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL
diff
) and active efflux clearance (CL
active
) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL
diff
, and efflux clearance is the sum of CL
diff
, CL
active
, and bulk flow clearance (CL
bulk
). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CL
bulk
of 0.01 ml/min, CL
active
was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.
Integration of a Transposon Tn
1
-Encoded Inhibitor-Resistant β-Lactamase Gene,
bla
TEM-67
from
Proteus mirabilis
, into the
Escherichia coli
Chromosome
Authors: Naas Thierry , Zerbib Marie , Girlich Delphine , Nordmann Patrice
Published: December 2002

Proteus mirabilis
NEL-1 was isolated from a urine sample of a patient hospitalized in a long-term care facility. Strain NEL-1 produced a β-lactamase with a pI of 5.2 conferring resistance to amoxicillin and amoxicillin-clavulanic acid. Sequencing of a PCR amplicon by using TEM-specific primers revealed a novel
bla
TEM
gene,
bla
TEM-67
. TEM-67 was an IRT-1-like TEM derivative related to TEM-65 (Lys39, Cys244) with an additional Leu21Ile amino acid substitution in the leader peptide. The biochemical properties of TEM-67 were equivalent to those described for TEM-65. Analysis of sequences surrounding
bla
TEM-67
revealed that it was located on a transposon, Tn
1
, which itself was located on a 48-kb non-self-transferable plasmid, pANG-1. Electroporation of plasmid pANG-1 into
Escherichia coli
DH10B resulted in the integration of
bla
TEM-67
into the chromosome, whereas it remained episomal in the
P. mirabilis
CIP103181 reference strain. Further characterization of pANG-1 revealed the presence of two identical sequences on both sides of Tn
1
that contained an IS
26
insertion sequence followed by a novel colicin gene,
colZ
, which had 20% amino acid identity with other colicin genes. The characterization of this novel TEM derivative provides further evidence for the large diversity of plasmid-encoded β-lactamases produced in
P. mirabilis
and for their spread to other enterobacterial species through transposable-element-mediated events.
A Clonal Lineage of VanA-Type
Enterococcus faecalis
Predominates in Vancomycin-Resistant Enterococci Isolated in New Zealand
Authors: Manson Janet M. , Keis Stefanie , Smith John M. B. , Cook Gregory M.
Published: December 2002

Avoparcin was used as a feed additive in New Zealand broiler production from 1977 until June 2000. We report here on the effects of the usage and discontinuation of avoparcin on the prevalence of vancomycin-resistant enterococci (VRE) in broilers. Eighty-two VRE isolates were recovered from poultry fecal samples between 2000 and mid-2001. VRE isolates were only obtained from broiler farms that were using, or had previously used, avoparcin as a dietary supplement. Of these VRE isolates, 73 (89%) were VanA-type
Enterococcus faecalis
and nine (11%) were VanA-type
Enterococcus faecium
. All
E. faecalis
isolates were found to have an identical or closely related pulsed-field gel electrophoresis (PFGE) pattern of
Sma
I-digested DNA and were susceptible to both ampicillin and gentamicin. The PFGE patterns of the nine
E. faecium
isolates were heterogeneous. All VRE contained both the
vanA
and
ermB
genes, which, regardless of species or PFGE pattern, resided on the same plasmid. Eighty-seven percent of the VRE isolates also harbored the
tet
(M) gene, while for 63 and 100%, respectively, of these isolates, the avilamycin and bacitracin MICs were high (≥256 μg/ml). Five of eight vancomycin-resistant
E. faecalis
isolates recovered from humans in New Zealand revealed a PFGE pattern identical or closely related to that of the
E. faecalis
poultry VRE isolates. Molecular characterization of Tn
1546
-like elements from the VRE showed that identical transposons were present in isolates from poultry and humans. Based on the findings presented here, a clonal lineage of VanA-type
E. faecalis
dominates in VRE isolated from poultry and humans in New Zealand.
Ribonucleoside Analogue That Blocks Replication of Bovine Viral Diarrhea and Hepatitis C Viruses in Culture
Authors: Stuyver Lieven J. , Whitaker Tony , McBrayer Tamara R. , Hernandez-Santiago Brenda I. , Lostia Stefania , Tharnish Phillip M. , Ramesh Mangala , Chu Chung K. , Jordan Robert , Shi Junxing , Rachakonda Suguna , Watanabe Kyoichi A. , Otto Michael J. , Schinazi Raymond F.
Published: December 2002

A base-modified nucleoside analogue, β-
d
-N
4
-hydroxycytidine (NHC), was found to have antipestivirus and antihepacivirus activities. This compound inhibited the production of cytopathic bovine viral diarrhea virus (BVDV) RNA in a dose-dependant manner with a 90% effective concentration (EC
90
) of 5.4 μM, an observation that was confirmed by virus yield assays (EC
90
= 2 μM). When tested for hepatitis C virus (HCV) replicon RNA reduction in Huh7 cells, NHC had an EC
90
of 5 μM on day 4. The HCV RNA reduction was incubation time and nucleoside concentration dependent. The in vitro antiviral effect of NHC was additive with recombinant alpha interferon-2a and could be prevented by the addition of exogenous cytidine and uridine but not of other natural ribo- or 2′-deoxynucleosides. When HCV RNA replicon cells were cultured in the presence of increasing concentrations of NHC (up to 40 μM) for up to 45 cell passages, no resistant replicon was selected. Similarly, resistant BVDV could not be selected after 20 passages. NHC was phosphorylated to the triphosphate form in Huh7 cells, but in cell-free HCV NS5B assays, synthetic NHC-triphosphate (NHC-TP) did not inhibit the polymerization reaction. Instead, NHC-TP appeared to serve as a weak alternative substrate for the viral polymerase, thereby changing the mobility of the product in polyacrylamide electrophoresis gels. We speculate that incorporated nucleoside analogues with the capacity of changing the thermodynamics of regulatory secondary structures (with or without introducing mutations) may represent an important class of new antiviral agents for the treatment of RNA virus infections, especially HCV.
Roles of
Mycobacterium smegmatis
d
-Alanine:
d
-Alanine Ligase and
d
-Alanine Racemase in the Mechanisms of Action of and Resistance to the Peptidoglycan Inhibitor
d
-Cycloserine
Authors: Feng Zhengyu , Barletta Raúl G.
Published: December 2002

d-
Cycloserine (DCS) targets the peptidoglycan biosynthetic enzymes
d-
alanine racemase (Alr) and
d-
alanine:
d-
alanine ligase (Ddl). Previously, we demonstrated that the overproduction of Alr in
Mycobacterium smegmatis
determines a DCS resistance phenotype. In this study, we investigated the roles of both Alr and Ddl in the mechanisms of action of and resistance to DCS in
M. smegmatis
. We found that the overexpression of either the
M. smegmatis
or the
Mycobacterium tuberculosis ddl
gene in
M. smegmatis
confers resistance to DCS, but at lower levels than the overexpression of the
alr
gene. Furthermore, a strain overexpressing both the
alr
and
ddl
genes displayed an eightfold-higher level of resistance. To test the hypothesis that inhibition of Alr by DCS decreases the intracellular pool of
d-
alanine, we determined the alanine pools in
M. smegmatis
wild-type and recombinant strains with or without DCS treatment. Alr-overproducing strain GPM14 cells not exposed to DCS displayed almost equimolar amounts of
l-
and
d-
alanine in the steady state. The wild-type strain and Ddl-overproducing strains contained a twofold excess of
l-
over
d-
alanine. In all strains, DCS treatment led to a significant accumulation of
l-
alanine and a concomitant decease of
d-
alanine, with approximately a 20-fold excess of
l-
alanine in the Ddl-overproducing strains. These data suggest that Ddl is not significantly inhibited by DCS at concentrations that inhibit Alr. This study is of significance for the identification of the lethal target(s) of DCS and the development of novel drugs targeting the
d-
alanine branch of mycobacterial peptidoglycan biosynthesis.
High-Throughput Growth Assay forToxoplasma gondiiUsing Yellow Fluorescent Protein
Authors: Gubbels Marc-Jan , Li Catherine , Striepen Boris
Published: December 2002

A high-throughput growth assay for the protozoan parasiteToxoplasma gondiiwas developed based on a highly fluorescent transgenic parasite line. These parasites are stably transfected with a tandem yellow fluorescent protein (YFP) and are 1,000 times more fluorescent than the wild type. Parasites were inoculated in optical-bottom 384-well culture plates containing a confluent monolayer of host cells, and growth was monitored by using a fluorescence plate reader. The signal was linearly correlated with parasite numbers over a wide array. Direct comparison of the YFP growth assay with the β-galactosidase growth assay by using parasites expressing both reporters demonstrated that the assays' sensitivities were comparable but that the accuracy of the YFP assay was higher, especially at higher numbers of parasites per well. Determination of the 50%-inhibitory concentrations of three known growth-inhibiting drugs (cytochalasin D, pyrimethamine, and clindamycin) resulted in values comparable to published data. The delayed parasite death kinetics of clindamycin could be measured without modification of the assay, making this assay very versatile. Additionally, the temperature-dependent effect of pyrimethamine was assayed in both wild-type and engineered drug-resistant parasites. Lastly, the development of mycophenolic acid resistance after transfection of a resistance gene inT. gondiiwas followed. In conclusion, the YFP growth assay limits pipetting steps to a minimum, is highly versatile and amendable to automation, and should enable rapid screening of compounds to fulfill the need for more efficient and less toxic antiparasitic drugs.
Contributions of Antibiotic Penetration, Oxygen Limitation, and Low Metabolic Activity to Tolerance of
Pseudomonas aeruginosa
Biofilms to Ciprofloxacin and Tobramycin
Authors: Walters Marshall C. , Roe Frank , Bugnicourt Amandine , Franklin Michael J. , Stewart Philip S.
Published: December 2002

The roles of slow antibiotic penetration, oxygen limitation, and low metabolic activity in the tolerance of
Pseudomonas aeruginosa
in biofilms to killing by antibiotics were investigated in vitro. Tobramycin and ciprofloxacin penetrated biofilms but failed to effectively kill the bacteria. Bacteria in colony biofilms survived prolonged exposure to either 10 μg of tobramycin ml
−1
or 1.0 μg of ciprofloxacin ml
−1
. After 100 h of antibiotic treatment, during which the colony biofilms were transferred to fresh antibiotic-containing plates every 24 h, the log reduction in viable cell numbers was only 0.49 ± 0.18 for tobramycin and 1.42 ± 0.03 for ciprofloxacin. Antibiotic permeation through colony biofilms, indicated by a diffusion cell bioassay, demonstrated that there was no acceleration in bacterial killing once the antibiotics penetrated the biofilms. These results suggested that limited antibiotic diffusion is not the primary protective mechanism for these biofilms. Transmission electron microscopic observations of antibiotic-affected cells showed lysed, vacuolated, and elongated cells exclusively near the air interface in antibiotic-treated biofilms, suggesting a role for oxygen limitation in protecting biofilm bacteria from antibiotics. To test this hypothesis, a microelectrode analysis was performed. The results demonstrated that oxygen penetrated 50 to 90 μm into the biofilm from the air interface. This oxic zone correlated to the region of the biofilm where an inducible green fluorescent protein was expressed, indicating that this was the active zone of bacterial metabolic activity. These results show that oxygen limitation and low metabolic activity in the interior of the biofilm, not poor antibiotic penetration, are correlated with antibiotic tolerance of this
P. aeruginosa
biofilm system.
Comparison of Anti-Hepatitis B Virus Activities of Lamivudine and Clevudine by a Quantitative Assay
Authors: Abdelhamed Ayman M. , Kelley Colleen M. , Miller Thomas G. , Furman Phillip A. , Cable Edward E. , Isom Harriet C.
Published: December 2002

In this study, we used a quantitative assay to measure the concentration-dependent effects of antivirals on extracellular hepatitis B virus (HBV) DNA as well as on different cytoplasmic and nuclear forms of HBV DNA that participate in HBV replication. HBV recombinant baculovirus, which efficiently delivers the HBV genome to HepG2 cells, was used for this study because (i) antivirals can be administered prior to initiation of HBV infection or after HBV infection and (ii) sufficiently high HBV replication levels are achieved that HBV covalently closed circular (CCC) DNA can be easily detected and individual HBV DNA species can be quantitatively analyzed separately from total HBV DNA. The results showed that the levels of HBV replicative intermediate and extracellular DNA decreased in a concentration-dependent fashion following antiviral treatment. The 50% effective concentration (EC50) and EC90values and the Hill slopes differed for the different HBV DNA species analyzed. The data clearly indicated that (i) nuclear HBV DNAs are more resistant to antiviral therapy than cytoplasmic or extracellular HBV DNAs and (ii) nuclear HBV CCC DNA is more resistant than the nuclear relaxed circular form. This report presents the first in vitro comparison of the effects of two antivirals administered prior to initiation of HBV infection and the first thorough in vitro quantitative study of concentration-dependent antiviral effects on HBV CCC DNA.
In34, a Complex In5 Family Class 1 Integron Containing orf513 and
dfrA10
Authors: Partridge Sally R. , Hall Ruth M.
Published: December 2002

A complex class 1 integron, In34, found in a conjugative plasmid from a multidrug-resistant
Klebsiella pneumoniae
strain isolated in 1997 at a hospital in Sydney, Australia, was shown to have a backbone related to that of In2, which belongs to the In5 family. In In34, the
aadB
gene cassette replaces the
aadA1a
cassette in In2, and two additional resistance genes,
dfrA10
and
aphA1
, that are not part of a gene cassette are present. The
aphA1
gene is in a Tn
4352
-like transposon that is located in the
tniA
gene. The
dfrA10
gene lies adjacent to a 2,154-bp DNA segment, known as the common region, that contains an open reading frame predicting a product of 513 amino acids (Orf513). Orf513 is 66 and 55% identical to the products of two further open reading frames that, like the common region, are found adjacent to antibiotic resistance genes. A 27-bp conserved sequence was found at one end of each type of common region. The loss of
dfrA10
due to homologous recombination between flanking direct repeats and incorporation of the excised circle by homologous recombination were demonstrated. Part of In34 is identical to the sequenced portion of In7, which is from a multidrug-resistant
Escherichia coli
strain that had been isolated 19 years earlier in the same hospital. In34 and In7 are in plasmids that contain the same six resistance genes conferring resistance to ampicillin, chloramphenicol, gentamicin, kanamycin, neomycin, tobramycin, trimethoprim, and sulfonamides, but the plasmid backbones appear to be unrelated, suggesting that translocation of a multiple-drug-resistance-determining region as well as horizontal transfer may have occurred.
Activities of Moxifloxacin Alone and in Combination with Other Antimicrobial Agents against Multidrug-Resistant
Mycobacterium tuberculosis
Infection in BALB/c Mice
Authors: Fattorini Lanfranco , Tan Dejiang , Iona Elisabetta , Mattei Maurizio , Giannoni Federico , Brunori Lara , Recchia Simona , Orefici Graziella
Published: December 2002

The activity of moxifloxacin was enhanced by the addition of ethionamide but not by that of cycloserine, thiacetazone, capreomycin,
para
-aminosalicylic acid, or linezolid in BALB/c mice infected with a strain of
Mycobacterium tuberculosis
resistant to isoniazid, rifampin, and six other drugs. These observations are important for the therapy of multidrug-resistant tuberculosis.
Clindamycin Modulates Inflammatory-Cytokine Induction in Lipopolysaccharide-Stimulated Mouse Peritoneal Macrophages
Authors: Nakano Tetsuji , Hiramatsu Kazufumi , Kishi Kenji , Hirata Norio , Kadota Jun-ichi , Nasu Masaru
Published: December 2002

We investigated the mechanism by which clindamycin (CLI) modulates cytokine induction after lipopolysaccharide (LPS) stimulation. Although CLI decreased the intracellular expression levels of tumor necrosis factor alpha and interleukin 1β (IL-1β) and increased IL-6 expression in macrophages, cytokine mRNA expression levels were similar in CLI-treated and untreated groups. Our findings suggest that CLI modulates cytokine production in LPS-stimulated macrophages.
Penetration of Fosfomycin into Inflammatory Lesions in Patients with Cellulitis or Diabetic Foot Syndrome
Authors: Legat F. J. , Maier A. , Dittrich P. , Zenahlik P. , Kern T. , Nuhsbaumer S. , Frossard M. , Salmhofer W. , Kerl H. , Müller M.
Published: December 2002

We investigated the distribution of the broad-spectrum antibiotic fosfomycin in infected soft tissue of patients with uncomplicated cellulitis of the lower extremities or diabetic foot infection using in vivo microdialysis. Our findings suggest that fosfomycin exhibits good and similar penetration into the fluid in the interstitial space in inflamed and noninflamed soft tissue in patients.
Synergistic Lethal Effect of a Combination of Phage Lytic Enzymes with Different Activities on Penicillin-Sensitive and -Resistant
Streptococcus pneumoniae
Strains
Authors: Loeffler J. M. , Fischetti V. A.
Published: December 2002

Pal and Cpl-1, two purified bacteriophage lytic enzymes, were tested for their in vitro activity, alone and in combination, against several serotypes of
Streptococcus pneumoniae
, including penicillin-resistant strains. The enzymes demonstrated synergism in their ability to cleave the bacterial peptidoglycan and thus may be more efficient for the prevention and elimination of pneumococcal colonization.
In Vivo Selection of
Campylobacter
Isolates with High Levels of Fluoroquinolone Resistance Associated with
gyrA
Mutations and the Function of the CmeABC Efflux Pump
Authors: Luo Naidan , Sahin Orhan , Lin Jun , Michel Linda O. , Zhang Qijing
Published: December 2002

Enrofloxacin treatment of chickens infected with fluoroquinolone(FQ)-sensitive
Campylobacter
promoted the emergence of FQ-resistant
Campylobacter
mutants which propagated in the intestinal tract and recolonized the chickens. The recovered isolates were highly resistant to quinolone antibiotics but remained susceptible to non-FQ antimicrobial agents. Specific single-point mutations in the
gyrA
gene and the function of the CmeABC efflux pump were linked to the acquired FQ resistance. These results reveal that
Campylobacter
is hypermutable in vivo under the selection pressure of FQ and highlight the need for the prudent use of FQ antibiotics.
Comparison of Linezolid Activities under Aerobic and Anaerobic Conditions against Methicillin-Resistant
Staphylococcus aureus
and Vancomycin-Resistant
Enterococcus faecium
Authors: Gunderson Brent W. , Ibrahim Khalid H. , Peloquin Charles A. , Hovde Laurie B. , Rotschafer John C.
Published: December 2002

Methicillin-resistant
Staphylococcus aureus
and vancomycin-resistant
Enterococcus faecium
were exposed to linezolid (MIC of 2 mg/liter) under aerobic or anaerobic conditions in an in vitro pharmacodynamic model. Drug concentration and half-life were adjusted to simulate clinical dosing (600 mg twice daily) of linezolid. Linezolid produced a 2-log
10
killing at 24 h, and rates of killing against each of these facultative organisms as measured by mean survival time appeared similar under aerobic and anaerobic conditions.