bluuebunny/crossref_metadata_2025 huggingface dataset:
At-wavelength characterization of an extreme ultraviolet camera from low to mid-spatial frequencies with a compact laser plasma source
Authors: Ray-Chaudhuri A. K. , Krenz K. D. , Fields C. H.
Published: July 2002

The final alignment and characterization of an extreme ultraviolet (EUV) lithographic projection optics system must be performed at the operating wavelength in order to account for errors associated with the combined effect of multilayer coating and substrate fabrication error. Two complementary metrology techniques have been developed which can operate on a compact laser plasma source: EUV lateral shear interferometry (LSI) and aerial image monitoring (AIM). LSI quantifies residual low spatial frequency wave front errors associated with the “figure” of each optical element. To characterize the effect of mid-spatial frequency errors that lead to scatter in the image plane, an EUV aerial image monitor was employed. EUV interferometry was compared to visible light interferometry measurements of the optical system and was found to be in reasonable agreement for low spatial frequency errors. The contrast as measured by AIM and photoresist exposures indicates an additional reduction of contrast associated with scatter due to large mid-spatial frequency errors.
Dry etching of InP using a CH3Cl/Ar/H2 gas mixture with electron-cyclotron-resonance excitation
Authors: Nozawa Hiroshi , Shibata Tomohiro , Tamamura Toshiaki
Published: July 2002

We have investigated the etching characteristics of InP etched with a CH3Cl/Ar/H2 gas mixture with electron-cyclotron-resonance excitation and compared them with those for a CH4/Ar/H2 gas mixture. Some advantages of CH3Cl/Ar/H2 over the CH4/Ar/H2 are found. A smooth etched surface without etch residue is obtained at 120 °C and above. Etch residue, which is drop shaped and originates from the preferential desorption of phosphorus, is inevitably generated when the CH4/Ar/H2 is used. The etch rate (15–25 nm/min at the temperatures of 120–175 °C) is larger than in CH4/Ar/H2 etching. This etch rate is controllable for fine structure fabrication, such as the grating in a semiconductor laser diode, and successful fabrication of a grating with 150 nm pitch and 30 nm depth is demonstrated.
Stretch and align virus in nanometer scale on an atomically flat surface
Authors: Hu J. , Zhang Z.-H. , Ouyang Z.-Q. , Chen S.-F. , Li M.-Q. , Yang F.-J.
Published: July 2002

Manipulation of macromolecules in nanometer scale is becoming an interesting research field. An approach to manipulate supramolecular assemblies is reported in this article. Linear phage viruses were aligned in one direction on atomically flat surfaces by a special method called “molecular combing.” Atomic force microscopy was used to check the results. Most of the phage strands were found to be stretch straight from one end to another. A related mechanism is also discussed.
Luminescence from erbium implanted silicon–germanium quantum wells
Authors: Huda M. Q. , Evans-Freeman J. H. , Peaker A. R. , Houghton D. C. , Nejim A.
Published: July 2002

We have investigated the luminescence emitted at 1.54 μm from erbium-implanted strained ultrahigh vacuum chemical vapor deposition-grown (UHVCVD-grown) Si1−xGex quantum wells. Germanium fractions of up to 13% were used, and all well widths were below the critical thickness for pseudomorphic growth. A preliminary study was carried out on Si1−xGex quantum wells implanted with amorphizing doses of silicon at 77 K in order to study the regrowth across the interfaces, and subsequent structural and optical recovery. After amorphization and regrowth by a two stage anneal process, transmission electron microscopy (TEM) clearly showed the presence of the quantum wells, with sharp contrast. X-ray diffraction (XRD) studies showed that good regrowth has been achieved, with line widths very similar to the original material. However, the photoluminescence (PL) was found to be dependent upon the duration of the first anneal. Increasing the anneal time resulted in PL spectra being dominated by broad signals between 0.9 and 0.97 eV associated with structural defects. High concentrations of erbium were incorporated into the strained Si1−xGex quantum wells by implantation and solid phase epitaxial regrowth. TEM and XRD studies showed that the quantum wells retained their structure, with negligible segregation or diffusion of the germanium during the recrystallization. Erbium-related emission centered at 1.54 μm was observed in the implanted Si1−xGex layers after regrowth, and generally found to be of similar intensity as that in bulk silicon implanted with more than an order of magnitude higher dose of erbium.
Submicrometer transmission mask fabricated by low-temperature SF6/O2 reactive ion etching and focused ion beam
Authors: Sheng H. Y. , Fujita D. , Ohgi T. , Okamoto H. , Nejoh H.
Published: July 2002

A novel technique is presented to fabricate a silicon submicrometer transmission mask for nanofabrication. One of the applications of the mask is to fabricate a single electron transistor using an ultrahigh vacuum scanning tunneling microscope. The mask fabrication processes involve KOH wet etching, electron beam lithography, low-temperature SF6/O2 plasma-assisted reactive ion etching and focused ion beam techniques. Using this method, we fabricated masks with pattern sizes of 2.5×2.5 mm2 and opaque parts of submicrometer scale. After the evaporation, by using the mask a submicrometer gap on the metal pattern can be obtained.
Cold cathode field emitter array on a quadrupole mass spectrometer: Route to miniaturization
Authors: Felter T. E.
Published: July 2002

We have improved the quadrupole mass spectrometer by substituting the conventional hot filament electron source by a field emitter array (FEA). Elimination of the hot filament avoids a number of common problems, including thermal cracking of delicate molecules, outgassing of the filament itself and nearby components, high power requirements for the filament, large size, stray light, stray magnetic fields, contamination by thoria and tungsten, and a long warm-up time. The advantages are clearest for portable applications where power requirements dominate. Here, the power savings are not just in eliminating the filament supply, but more important in reducing the largest component of the system, the vacuum pump. This comes about because the filament is the primary gas load and because chemical reactions taking place on it require fast pumping to keep the products from interfering with the spectra. Comparison between hot filament and cold cathode FEA ionization is made using a quadrupole mass spectrometer fitted with both electron sources, independently controlled. The FEA advantage is strongest when the ultrahigh vacuum system is throttled to a low pumping speed, mimicking a portable system with a small pump. FEAs also enable miniaturization and a corresponding decrease in pump size. Moreover, with miniaturization, shorter mean free paths and consequently higher working pressures can be tolerated further decreasing pump requirements.
Cantilever technique for the preparation of cross sections for transmission electron microscopy using a focused ion beam workstation
Authors: Langford R. M. , Reeves C. M. , Goodall J. G. , Findlay J. , Jeffree C. E.
Published: July 2002

A new method for the preparation of cross sections for transmission electron microscopy using a focused ion beam workstation is presented. The new technique consists of micromachining a freestanding cantilever into which a membrane for transmission electron microscopy is milled. An advantage of this approach over the trench and lift out focused ion beam procedures for the preparation of cross sections for transmission electron microscopy is that the resulting cross sections can be both tilted through large angles (+45°) without the electron path becoming obstructed and they can be returned to the focused ion beam system for further thinning.
Determination of pore size distribution in thin films by ellipsometric porosimetry
Authors: Baklanov M. R. , Mogilnikov K. P. , Polovinkin V. G. , Dultsev F. N.
Published: July 2002

We show that ellipsometric porosimetry can be used for the measurement of the pore size distribution in thin porous films deposited on top of any smooth solid substrate. In this method, in situ ellipsometry is used to determine the amount of adsorptive, which is adsorbed/condensed in the film. Changes in refractive index and film thickness are used to calculate the quantity of adsorptive present in the film. Room temperature porosimetry based on adsorption of vapor of organic solvents has been developed. In this article, a method of calculation of pore size distribution and results of measurements on mesoporous and microporous xerogel films is discussed. Examination of the validity of the Gurvitsch rule for various organic adsorptives (toluene, heptane, and carbon tetrachloride) is carried out to assess the reliability of measurements of pore size distributions by ellipsometric porosimetry.
Theoretical study of GaN molecular beam epitaxy growth using ammonia: A rate equation approach
Authors: Fu Wenning , Venkat Rama
Published: July 2002

III–V nitrides are intensely researched for optoelectronic applications spanning the entire visible spectrum. In spite of realization of commercial devices and advances in processing of materials and devices, the understanding of the processing and epitaxial growth of these materials is incomplete. In this study, a rate equation approach is proposed based on physically sound surface processes to investigate the molecular beam epitaxy growth of GaN using ammonia. A surface riding layer of Ga and ammonia and its associated dynamics such as incorporation of Ga and N in to the crystal and desorption are included in the model. Rates of all surface processes are assumed Arrhenius type. The simulated Ga incorporation rate as a function of ammonia pressure and substrate temperature are in excellent agreement with the experimental data. Ga incorporation increases with increasing NH3 overpressure and saturates at a maximum value at large NH3 overpressure. The Ga incorporation rate exhibits a peak at 820 °C due to competition between thermally activated pyrolysis of NH3 and reevaporation of Ga from the surface. The simulated Ga desorption parameter versus time data is also in good agreement with the experimental data. These observations will be explained based on the interplay of competing surface processes such as reevaporation and incorporation.
Organic Composition of C/1999 S4 (LINEAR): A Comet Formed Near Jupiter?
Authors: Mumma M. J. , Dello Russo N. , DiSanti M. A. , Magee-Sauer K. , Novak R. E. , Brittain S. , Rettig T. , McLean I. S. , Reuter D. C. , Xu Li-H.
Published: July 2002

In the current paradigm, Oort cloud comets formed in the giant planets' region of the solar nebula, where temperatures and other conditions varied greatly. The measured compositions of four such comets (Halley, Hyakutake, Hale-Bopp, and Lee) are consistent with formation from interstellar ices in the cold nebular region beyond Uranus. The composition of comet C/1999 S4 (LINEAR) differs greatly, which suggests that its ices condensed from processed nebular gas, probably in the Jupiter-Saturn region. Its unusual organic composition may require reevaluation of the prebiotic organic material delivered to the young Earth by comets.
Selection Forces and Constraints on Retroviral Sequence Variation
Authors: Overbaugh Julie , Bangham Charles R. M.
Published: July 2002

All retroviruses possess a highly error-prone reverse transcriptase, but the extent of the consequent sequence diversity and the rate of evolution differ greatly among retroviruses. Because of the high mutability of retroviruses, it is not the generation of new viral variants that limits the extent of diversity and the rate of evolution of retroviruses, but rather the selection forces that act on these variants. Here, we suggest that two selection forces—the immune response and the limited availability of appropriate target cells during transmission and persistence—are chiefly responsible for the observed sequence diversity in untreated retroviral infections. We illustrate these aspects of positive selection by reference to specific lentiviruses [human and simian immunodeficiency viruses (HIV and SIV)] and oncoviruses [feline leukemia virus (FeLV) and human T cell leukemia virus (HTLV)] that differ in their extent of variation and in disease outcomes.
Rates of Evolution in Ancient DNA from Adélie Penguins
Authors: Lambert D. M. , Ritchie P. A. , Millar C. D. , Holland B. , Drummond A. J. , Baroni C.
Published: July 2002

Well-preserved subfossil bones of Adélie penguins,
Pygoscelis adeliae
, underlie existing and abandoned nesting colonies in Antarctica. These bones, dating back to more than 7000 years before the present, harbor some of the best-preserved ancient DNA yet discovered. From 96 radiocarbon-aged bones, we report large numbers of mitochondrial haplotypes, some of which appear to be extinct, given the 380 living birds sampled. We demonstrate DNA sequence evolution through time and estimate the rate of evolution of the hypervariable region I using a Markov chain Monte Carlo integration and a least-squares regression analysis. Our calculated rates of evolution are approximately two to seven times higher than previous indirect phylogenetic estimates.
Susceptibility Genes: Pointing a Way to Prevention?
Authors: Kahn Patricia
Published: July 2002

A host of other genes as well as factors in the outside world can affect the activity of a disease gene. This complexity has a bright side: If environmental factors shaping the effects of a disease gene can be tracked down, they can provide keys for treatment and prevention—a strategy now being tried for asthma and juvenile diabetes.
Identification of Subunits of the Anaphase-Promoting Complex of
Saccharomyces cerevisiae
Authors: Zachariae Wolfgang , Shin Tae Ho , Galova Marta , Obermaier Brigitte , Nasmyth Kim
Published: July 2002

Entry into anaphase and proteolysis of B-type cyclins depend on a complex containing the tetratricopeptide repeat proteins Cdc16p, Cdc23p, and Cdc27p. This particle, called the anaphase-promoting complex (APC) or cyclosome, functions as a cell cycle-regulated ubiquitin-protein ligase. Two additional subunits of the budding yeast APC were identified: The largest subunit, encoded by the
APC1
gene, is conserved between fungi and vertebrates and shows similarity to BIMEp from
Aspergillus nidulans
. A small heat-inducible subunit is encoded by the
CDC26
gene. The yeast APC is a 36
S
particle that contains at least seven different proteins.
Long-Term Responses of River-Margin Vegetation to Water-Level Regulation
Authors: Nilsson Christer , Jansson Roland , Zinko Ursula
Published: July 2002

The long-term effect of water-level regulation on riparian plant communities was assessed for storage reservoirs and run-of-river impoundments. Soon after the onset of regulation, there were few species and sparse vegetation cover, regardless of whether the new water level intersected former upland or riparian vegetation. In the longer term, an impoverished vegetation was maintained by storage reservoirs, whereas in run-of-river impoundments, some community characteristics deteriorated and others recovered compared to adjacent free-flowing rivers.
STAT3 as an Adapter to Couple Phosphatidylinositol 3-Kinase to the IFNAR1 Chain of the Type I Interferon Receptor
Authors: Pfeffer Lawrence M. , Mullersman Jerald E. , Pfeffer Susan R. , Murti Aruna , Shi Wei , Yang Chuan He
Published: July 2002

STAT (signal transducers and activators of transcription) proteins undergo cytokine-dependent phosphorylation on serine and tyrosine. STAT3, a transcription factor for acute phase response genes, was found to act as an adapter molecule in signal transduction from the type I interferon receptor. STAT3 bound to a conserved sequence in the cytoplasmic tail of the IFNAR1 chain of the receptor and underwent interferon-dependent tyrosine phosphorylation. The p85 regulatory subunit of phosphatidylinositol 3-kinase, which activates a series of serine kinases, bound to phosphorylated STAT3 and subsequently underwent tyrosine phosphorylation. Thus, STAT3 acts as an adapter to couple another signaling pathway to the interferon receptor.
Do Habitat Conservation Plans Protect Endangered Species?
Authors: Shilling Fraser
Published: July 2002

The number of threatened and endangered (T&E) species in the United States is increasing monthly and critical habitat is constantly being destroyed. The number of newly listed T&E species greatly outweighs the number recovered from threatened extinction, and the federal and state governments demonstrate little desire to step in on behalf of species at risk. These ecological crises faced by endangered species (
1
) may be exacerbated by the application of one aspect of the Endangered Species Act (ESA)—habitat conservation plans (HCPs). Many T&E species will be at a crossroads over the next few years and the strength and use of the ESA will determine their fate.
A Giant Protease with Potential to Substitute for Some Functions of the Proteasome
Authors: Geier Elke , Pfeifer Günter , Wilm Matthias , Lucchiari-Hartz Maria , Baumeister Wolfgang , Eichmann Klaus , Niedermann Gabriele
Published: July 2002

An alanyl-alanyl-phenylalanyl-7-amino-4-methylcoumarin–hydrolyzing protease particle copurifying with 26
S
proteasomes was isolated and identified as tripeptidyl peptidase II (TPPII), a cytosolic subtilisin-like peptidase of unknown function. The particle is larger than the 26
S
proteasome and has a rod-shaped, dynamic supramolecular structure. TPPII exhibits enhanced activity in proteasome inhibitor–adapted cells and degrades polypeptides by exo- as well as predominantly trypsin-like endoproteolytic cleavage. TPPII may thus participate in extralysosomal polypeptide degradation and may in part account for nonproteasomal epitope generation as postulated for certain major histocompatibility complex class I alleles. In addition, TPPII may be able to substitute for some metabolic functions of the proteasome.
Mead Misrepresented
Authors: Orans Martin
Published: July 2002

The Fateful Hoaxing of Margaret Mead
A Historical Analysis of Her Samoan Research. Derek Freeman. Westview (Perseus), Boulder, CO, 1998. 291 pp. $24, C$34. ISBN 0-8133-3560-4.

Freeman argues that Margaret Mead's classic account of sexuality among young Samoan women resulted from her having been hoaxed by native informants and from the beliefs on behavior and biology that she shared with her mentor Franz Boas. Our reviewer finds Freeman's interpretations biased and unconvincing.
Current-Induced Insulator-Metal Transition and Pattern Formation in an Organic Charge-Transfer Complex
Authors: Kumai R. , Okimoto Y. , Tokura Y.
Published: July 2002

Organic molecular Mott insulators, in which carriers are localized as a result of the electron correlation, showed nonlinear electric conduction upon application of a high electric field along the molecular stacking axis. The current-driven low-resistive state of potassium 7,7,8,8-tetracyanoquinodimethanane was stabilized down to 2 kelvin, where a metallic path was visible with a microscope. The current flow caused a stripe-like periodic phase-segregation into the carrier-rich and carrier-poor regions along the current path.
Inhibition of the Interferon- Inducible Protein Kinase PKR by HCV E2 Protein
Authors: Taylor Deborah R. , Shi Stephanie T. , Romano Patrick R. , Barber Glen N. , Lai Michael M. C.
Published: July 2002

Most isolates of hepatitis C virus (HCV) infections are resistant to interferon, the only available therapy, but the mechanism underlying this resistance has not been defined. Here it is shown that the HCV envelope protein E2 contains a sequence identical with phosphorylation sites of the interferon-inducible protein kinase PKR and the translation initiation factor eIF2α, a target of PKR. E2 inhibited the kinase activity of PKR and blocked its inhibitory effect on protein synthesis and cell growth. This interaction of E2 and PKR may be one mechanism by which HCV circumvents the antiviral effect of interferon.
Protamine-Induced Condensation and Decondensation of the Same DNA Molecule
Authors: Brewer Laurence R. , Corzett Michele , Balhorn Rod
Published: July 2002

The DNA in sperm and certain viruses is condensed by arginine-rich proteins into toroidal subunits, a form of packaging that inactivates their entire genome. Individual DNA molecules were manipulated with an optical trap to examine the kinetics of torus formation induced by the binding of protamine and a subset of its DNA binding domain, Arg
6
. Condensation and decondensation experiments with λ-phage DNA show that toroid formation and stability are influenced by the number of arginine-rich anchoring domains in protamine. The results explain why protamines contain so much arginine and suggest that these proteins must be actively removed from sperm chromatin after fertilization.
Role of the Guanosine Triphosphatase Rac2 in T Helper 1 Cell Differentiation
Authors: Li Baiyong , Yu Hong , Zheng Wei-ping , Voll Reinhard , Na Songqing , Roberts Andrew W. , Williams David A. , Davis Roger J. , Ghosh Sankar , Flavell Richard A.
Published: July 2002

T helper 1 (T
H
1) cells mediate cellular immunity, whereas T
H
2 cells potentiate antiparasite and humoral immunity. We used a complementary DNA subtraction method, representational display analysis, to show that the small guanosine triphosphatase Rac2 is expressed selectively in murine T
H
1 cells. Rac induces the interferon-γ (IFN-γ) promoter through cooperative activation of the nuclear factor kappa B and p38 mitogen-activated protein kinase pathways. Tetracycline-regulated transgenic mice expressing constitutively active Rac2 in T cells exhibited enhanced IFN-γ production. Dominant-negative Rac inhibited IFN-γ production in murine T cells. Moreover, T cells from Rac2
−/−
mice showed decreased IFN-γ production under T
H
1 conditions in vitro. Thus, Rac2 activates T
H
1-specific signaling and IFN-γ gene expression.
Methionine Interference in Rapamycin Production Involves Repression of Demethylrapamycin Methyltransferase and
S
-Adenosylmethionine Synthetase
Authors: Kim Wan-Seop , Wang Yi , Fang Aiqi , Demain Arnold L.
Published: July 2002

In a chemically defined medium,
l
-methionine decreased production of rapamycin and increased that of demethylrapamycin. Growth with
l
-methionine yielded cells with a lower ability to convert demethylrapamycin to rapamycin and decreased the level of
S
-adenosylmethionine synthetase and
S
-adenosylmethionine. Thus, methionine represses at least one methyltransferase of rapamycin biosynthesis and
S
-adenosylmethionine synthetase.
A Comparative In Vitro Surveillance Study of Gemifloxacin Activities against 2,632 Recent
Streptococcus pneumoniae
Isolates from across Europe, North America, and South America
Authors: Hoban D. J. , Bouchillon S. K. , Karlowsky J. A. , Johnson J. L. , Butler D. L. , Miller L. A. , Poupard J. A. ,   The Gemifloxacin Surveillance Study Research Group
Published: July 2002

From 1997 to 1999, 94 study centers in 15 European, 3 North American, and 2 South American countries contributed 2,632 isolates of
Streptococcus pneumoniae
to an international antimicrobial susceptibility testing study. Only 62.0% of isolates were susceptible to penicillin, while 22.3% were penicillin intermediate and 15.6% were penicillin resistant. Resistance to trimethoprim-sulfamethoxazole (24.4%), azithromycin (26.0%), and clarithromycin (27.1%) was also highly prevalent. For the penicillin-resistant isolates (
n
= 411), the MICs at which 90% of isolates are inhibited (MIC
90
s) for gemifloxacin, levofloxacin, ofloxacin, clarithromycin, and azithromycin were 0.03, 1, 2, >16, and >64 μg/ml, respectively. Similarly, for isolates resistant to both azithromycin and clarithromycin (
n
= 649), gemifloxacin, levofloxacin, ofloxacin, and penicillin MIC
90
s were 0.03, 1, 2, and 4 μg/ml, respectively. Overall rates of resistance to trovafloxacin (0.3%), levofloxacin (0.3%), grepafloxacin (0.6%), and ofloxacin (0.7%) were low. For ofloxacin-intermediate and -resistant isolates (
n
= 142), gemifloxacin had the lowest MIC
90
(0.12 μg/ml) compared to the MIC
90
s of trovafloxacin (0.5 μg/ml), grepafloxacin (1 μg/ml), and levofloxacin (2 μg/ml). For all
S. pneumoniae
isolates tested, gemifloxacin MICs were ≤0.5 μg/ml, suggesting that gemifloxacin has the potential to be used as a treatment for pneumococcal infections, including those arising from isolates resistant to β-lactams and macrolides.
Gametocytocidal Activity and Synergistic Interactions of Riboflavin with Standard Antimalarial Drugs against Growth of
Plasmodium falciparum
In Vitro
Authors: Akompong Thomas , Eksi Saliha , Williamson Kim , Haldar Kasturi
Published: July 2002

Our previous studies have shown that riboflavin has activity against
Plasmodium falciparum
asexual-stage parasites in vitro. In the present study we examine the gametocytocidal activity of riboflavin and the interaction of riboflavin with some commonly used antimalarial drugs against the asexual forms of
P. falciparum
in vitro. The addition of riboflavin to
P. falciparum
cultures killed gametocytes at all stages, even those at late stages (III to V), which are not affected by many of the commonly used antimalarials. Combinations of riboflavin with mefloquine, pyrimethamine, and quinine showed a marked potentiation of the activities of these drugs against asexual-stage parasites in vitro. The combination of riboflavin with artemisinin was additive, while that with chloroquine was mildly antagonistic. High doses of riboflavin are used clinically to treat several inborn errors of metabolism with no adverse side effects. Its efficacy in combination with standard antimalarial drugs in treating and preventing the transmission of
P. falciparum
malaria can therefore be evaluated in humans.
Antibacterial Spectrum of a Novel Des-Fluoro(6) Quinolone, BMS-284756
Authors: Fung-Tomc Joan C. , Minassian Beatrice , Kolek Benjamin , Huczko Elizabeth , Aleksunes Lauren , Stickle Terry , Washo Thomas , Gradelski Elizabeth , Valera Lourdes , Bonner Daniel P.
Published: July 2002

The in vitro spectrum of a novel des-fluoro(6) quinolone, BMS-284756, was compared with those of five fluoroquinolones (trovafloxacin, moxifloxacin, levofloxacin, ofloxacin, and ciprofloxacin). BMS-284756 was among the most active and often was the most active quinolone against staphylococci (including methicillin-resistant strains), streptococci, pneumococci (including ciprofloxacin-nonsusceptible and penicillin-resistant strains), and
Enterococcus faecalis
. BMS-284756 inhibited ≈60 to ≈70% of the
Enterococcus faecium
(including vancomycin-resistant) strains and 90 to 100% of the
Enterobacteriaceae
strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint (≤4 μg/ml). Against the nonfermenters, BMS-284756 inhibited 90 to 100% of
Pseudomonas fluorescens
,
Pseudomonas stutzeri
,
Stenotrophomonas maltophilia
,
Flavobacterium
spp., and
Acinetobacter
spp. and 72% of
Pseudomonas aeruginosa
strains at 4 μg/ml. Against anaerobic bacteria, BMS-284756 was among the most active, inhibiting essentially all strains tested. It had very low MICs against the fastidious and atypical microbial species, in particular against mycoplasmas or ureaplasmas,
Borrelia burgdorferi
, chlamydia, and gonococci. These results indicate that with its broad antibacterial spectrum, BMS-284756 should be evaluated clinically for the treatment of community and nosocomial infections.
Toxicity of LY303366, an Echinocandin Antifungal, in Mice Pretreated with Glucocorticoids
Authors: Clemons Karl V. , Sobel Raymond A. , Stevens David A.
Published: July 2002

LY303366 is a semisynthetic derivative of the echinocandin class. During preclinical studies, lethal toxicity was observed in DBA/2 mice pretreated with a cortisone acetate dose followed by treatment with LY303366 at doses ranging from 12.5 to 50 mg/kg of body weight/day given intraperitoneally (i.p.). In the cortisone-treated, uninfected controls, 90% given LY303366 at 50 mg/kg died. Deaths occurred only in steroid-treated mice. In additional experiments, uninfected DBA/2 and CD-1 mice were pretreated with different glucocorticoids. Dosages were adjusted for comparative potency with cortisone and were given at one, two, or five times the equivalent cortisone dosage of 5 mg prior to treatment with LY303366 at 25 mg/kg/day given i.p. Lethal toxicity occurred in DBA/2 mice given hydrocortisone (1× or 2×), triamcinolone (1× or 5×), and cortisone. However, no mice pretreated with 1× or 5× dexamethasone died. In CD-1 mice, deaths occurred only in those given 5× triamcinolone; three of five died 2 days after the cessation of 10 days of LY303366 treatment. The causes of the deaths and why inbred DBA/2 mice are more sensitive than outbred CD-1 mice to the combined lethal effects of LY303366 and some glucocorticoids could not be determined histologically and remain unexplained. This is the first report of this toxicity of combination glucocorticoids and LY303366. Whether a similar toxicity might apply to the other compounds in the echinocandin class of antifungals and the species specificity require additional study. In addition, the clinical relevance of these observations in steroid-treated patients to the clinical safety of LY303366 and other echinocandins needs to be determined.
Single-Dose Pharmacokinetics and Safety of the Oral Antiviral Compound Adefovir Dipivoxil in Children Infected with Human Immunodeficiency Virus Type 1
Authors: Hughes Walter T. , Shenep Jerry L. , Rodman John H. , Fridland Arnold , Willoughby Rodney , Blanchard Suzette , Purdue Lynette , Coakley Dion F. , Cundy Kenneth C. , Culnane Mary , Zimmer Bonnie , Burchett Sandra , Read Jennifer S. ,   The Pediatric AIDS Clinical Trials Group
Published: July 2002

The acyclic phosphonate analog adefovir is a potent inhibitor of retroviruses, including human immunodeficiency virus (HIV) type 1, and, unlike some antiviral nucleosides, does not require the initial phosphorylation step for its activity. Two oral dosages of the adefovir prodrug adefovir dipivoxil were evaluated in a phase I study with children with HIV infection. A total of 14 patients were stratified into age groups ranging from 6 months to 18 years of age. Eight patients received 1.5 mg of adefovir dipivoxil per kg of body weight, and six patients received 3.0 mg of adefovir dipivoxil per kg. Serum samples were obtained at intervals during the 8 h postdosing and were analyzed for adefovir concentrations. Patients were monitored for adverse effects. All samples collected resulted in quantifiable levels of adefovir (lower limit of quantitation, 25 ng/ml) from each patient. The areas under the concentration-versus-time curves (AUCs) were similar (
P
= 0.85) for the 1.5- and 3.0-mg/kg doses, while the apparent oral clearance (CL/
F
) was significantly higher (
P
= 0.05) for the 3-mg/kg dose. Pharmacokinetic parameters differed by patient age. In comparing those children older and younger than the median age of 5.1 years, AUC (
P
= 0.03), maximum concentration of drug in serum (
P
= 0.004), and the concentration at 8 h postdosing (
P
= 0.02) were significantly lower for the younger children. There were no significant differences for apparent volume of distribution and CL/
F
normalized to body surface area, but there was a suggestive difference in half-life (
P
= 0.07) among the subjects in the older and younger age groups. No significant adverse events were encountered. These data provide the basis for a multidose phase II study of adefovir dipivoxil in HIV-infected infants and children.
Efficacy of SCH27899 in an Animal Model of Legionnaires' Disease Using Immunocompromised A/J Mice
Authors: Brieland Joan K. , Loebenberg David , Menzel Fred , Hare Roberta S.
Published: July 2002

The efficacy of SCH27899, a new everninomicin antibiotic, against replicativeLegionella pneumophilalung infections in an immunocompromised host was evaluated using a murine model of Legionnaires' disease. A/J mice were immunocompromised with cortisone acetate and inoculated intratracheally withL. pneumophilaserogroup 1 (105CFU per mouse). At 24 h postinoculation, mice were administered either SCH27899 (6 to 60 mg/kg [MPK] intravenously) or a placebo once daily for 5 days, and mortality and intrapulmonary growth ofL. pneumophilawere assessed. In the absence of SCH27899, there was 100% mortality inL. pneumophila-infected mice, with exponential intrapulmonary growth of the bacteria. In contrast, administration of SCH27899 at a dose of ≥30 MPK resulted in ≥90% survival of infected mice, which was associated with inhibition of intrapulmonary growth ofL. pneumophila. In subsequent studies, the efficacy of SCH27899 was compared to ofloxacin (OFX) and azithromycin (AZI). Administration of SCH27899, OFX, or AZI at a dose of ≥30 MPK once daily for 5 days resulted in ≥85% survival of infected mice and inhibition of intrapulmonary growth of the bacteria. However,L. pneumophilaCFU were recovered in lung homogenates following cessation of therapy with all three antibiotics. These studies demonstrate that SCH27899 effectively prevents fatal replicativeL. pneumophilalung infection in immunocompromised A/J mice by inhibition of intrapulmonary growth of the bacteria. However, in this murine model of pulmonary legionellosis, SCH27899, like OFX and AZI, was bacteriostatic.
Mechanism of Action of 1-β-
d
-2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-β-
d
-Dioxolane Guanosine
Authors: Furman Phillip A. , Jeffrey Jerry , Kiefer Laura L. , Feng Joy Y. , Anderson Karen S. , Borroto-Esoda Katyna , Hill Edgar , Copeland William C. , Chu Chung K. , Sommadossi Jean-Pierre , Liberman Irina , Schinazi Raymond F. , Painter George R.
Published: July 2002

(−)-β-
d
-2,6-Diaminopurine dioxolane (DAPD), is a nucleoside reverse transcriptase (RT) inhibitor with activity against human immunodeficiency virus type 1 (HIV-1). DAPD, which was designed as a water-soluble prodrug, is deaminated by adenosine deaminase to give (−)-β-
d
-dioxolane guanine (DXG). By using calf adenosine deaminase a

K
m

value of 15 ± 0.7 μM was determined for DAPD, which was similar to the

K
m

value for adenosine. However, the
k
cat
for DAPD was 540-fold slower than the
k
cat
for adenosine. In CEM cells and peripheral blood mononuclear cells exposed to DAPD or DXG, only the 5′-triphosphate of DXG (DXG-TP) was detected. DXG-TP is a potent alternative substrate inhibitor of HIV-1 RT. Rapid transient kinetic studies show the efficiency of incorporation for DXG-TP to be lower than that measured for the natural substrate, 2′-deoxyguanosine 5′-triphosphate. DXG-TP is a weak inhibitor of human DNA polymerases α and β. Against the large subunit of human DNA polymerase γ a

K
i

value of 4.3 ± 0.4 μM was determined for DXG-TP. DXG showed little or no cytotoxicity and no mitochondrial toxicity at the concentrations tested.
Evidence of Less Severe Aortic Valve Destruction after Treatment of Experimental Staphylococcal Endocarditis with Vancomycin and Dexamethasone
Authors: Siaperas Peter , Pefanis Angelos , Iliopoulos Dimitrios , Katsarolis Ioannis , Kyroudi-Voulgari Aspassia , Donta Ismini , Karayiannakos Panayiotis , Giamarellou Helen
Published: July 2002

The beneficial effects of therapy combining an antibiotic and dexamethasone have been reported in human studies on meningitis and in experimental studies on septic arthritis, nephritis, and endophthalmitis. Since most patients with staphylococcal endocarditis need a combination of medical and surgical treatment, the purpose of this study was to determine whether the addition of dexamethasone to vancomycin has any beneficial effect regarding the degree of valve tissue damage or the course of experimental aortic valve endocarditis caused by a methicillin-resistant strain of
Staphylococcus aureus
. Rabbits with catheter-induced aortic valve vegetations were randomly assigned to a control group and to groups receiving dexamethasone (0.5 mg/kg of body weight, intravenously [i.v.], twice a day [b.i.d]), vancomycin (30 mg/kg, i.v., b.i.d), or dexamethasone plus vancomycin, for a total of 10 doses (two doses per day for 5 days). The severity of valve tissue damage was significantly less in groups receiving vancomycin plus dexamethasone compared with that of the group receiving vancomycin alone (
P
< 0.001). The severity of tissue damage was inversely correlated with the mean polymorphonuclear leukocyte number in valve tissue. No statistically significant differences were observed between the vancomycin-treated group and the vancomycin-plus-dexamethasone-treated group in survival, blood culture sterilization rate, or reduction of the microbial burden (in CFU per gram) in valvular tissue. In conclusion, treatment with a combination of vancomycin and dexamethasone for 5 days reduces the severity of valve tissue damage in experimental staphylococcal aortic valve endocarditis. These findings could have significant implications in the treatment of staphylococcal endocarditis and deserve further confirmation in clinical trials.
Mdt(A), a New Efflux Protein Conferring Multiple Antibiotic Resistance in
Lactococcus lactis
and
Escherichia coli
Authors: Perreten Vincent , Schwarz Franziska V. , Teuber Michael , Levy Stuart B.
Published: July 2002

The
mdt
(A) gene, previously designated
mef214
, from
Lactococcus lactis
subsp.
lactis
plasmid pK214 encodes a protein [Mdt(A) (multiple drug transporter)] with 12 putative transmembrane segments (TMS) that contain typical motifs conserved among the efflux proteins of the major facilitator superfamily. However, it also has two C-motifs (conserved in the fifth TMS of the antiporters) and a putative ATP-binding site. Expression of the cloned
mdt
(A) gene decreased susceptibility to macrolides, lincosamides, streptogramins, and tetracyclines in
L. lactis
and
Escherichia coli
, but not in
Enterococcus faecalis
or in
Staphylococcus aureus
. Glucose-dependent efflux of erythromycin and tetracycline was demonstrated in
L. lactis
and in
E. coli
.
Mechanisms of Macrolide Resistance in Clinical Group B Streptococci Isolated in France
Authors: Fitoussi Frederic , Loukil Chawki , Gros Isabelle , Clermont Olivier , Mariani Patricia , Bonacorsi Stephane , Le Thomas Isabelle , Deforche Dominique , Bingen Edouard
Published: July 2002

Macrolide susceptibility was investigated in clinical group B streptococci obtained from neonates or pregnant women in 2000 in France. Of 490 consecutive isolates, 18% were resistant to erythromycin. The
erm
(B),
erm
(A) subclass
erm
(TR), and
mef
(A) genes were harbored by 47, 45, and 6% of these strains, respectively. Two isolates did not harbor
erm
or
mef
genes.
Interference between D30N and L90M in Selection and Development of Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1
Authors: Sugiura Wataru , Matsuda Zene , Yokomaku Yoshiyuki , Hertogs Kurt , Larder Brendan , Oishi Tsuyoshi , Okano Aiko , Shiino Teiichirou , Tatsumi Masashi , Matsuda Masakazu , Abumi Hanae , Takata Noboru , Shirahata Satoshi , Yamada Kaneo , Yoshikura Hiroshi , Nagai Yoshiyuki
Published: July 2002

We studied the evolutionary relationships between the two protease inhibitor (PI) resistance mutations, D30N and L90M, of human immunodeficiency virus type 1 (HIV-1). The former is highly specific for nelfinavir resistance, while the latter is associated with resistance to several PIs, including nelfinavir. Among patients with nelfinavir treatment failure, we found that D30N acquisition was strongly suppressed when L90M preexisted. Thus, D30N/L90M double mutations not only were detected in a very limited number of patients but also accounted for a minor fraction within each patient. In the disease course, the D30N and L90M clones readily evolved independently of each other, and later the D30N/L90M double mutants emerged. The double mutants appeared to originate from the D30N lineage but not from the L90M lineage, or were strongly associated with the former. However, their evolutionary pathways appeared to be highly complex and to still have something in common, as they always contained several additional polymorphisms, including L63P and N88D, as common signatures. These results suggest that D30N and L90M are mutually exclusive during the evolutionary process. Supporting this notion, the D30N/L90M mutation was also quite rare in a large clinical database. Recombinant viruses with the relevant mutations were generated and compared for the ability to process p55

gag

and p160

pol

precursor proteins as well as for their infectivity. L90M caused little impairment of the cleavage activities, but D30N was detrimental, although significant residual activity was observed. In contrast, D30N/L90M demonstrated severe impairment. Thus, the concept of mutual antagonism of the two mutations was substantiated biochemically and functionally.
Evolution of Primary Protease Inhibitor Resistance Mutations during Protease Inhibitor Salvage Therapy
Authors: Kantor Rami , Fessel W. Jeffrey , Zolopa Andrew R. , Israelski Dennis , Shulman Nancy , Montoya Jose G. , Harbour Michael , Schapiro Jonathan M. , Shafer Robert W.
Published: July 2002

In order to track the evolution of primary protease inhibitor (PI) resistance mutations in human immunodeficiency virus type 1 (HIV-1) isolates, baseline and follow-up protease sequences were obtained from patients undergoing salvage PI therapy who presented initially with isolates containing a single primary PI resistance mutation. Among 78 patients meeting study selection criteria, baseline primary PI resistance mutations included L90M (42% of patients), V82A/F/T (27%), D30N (21%), G48V (6%), and I84V (4%). Despite the switching of treatment to a new PI, primary PI resistance mutations present at the baseline persisted in 66 of 78 (85%) patients. D30N persisted less frequently than L90M (50% versus 100%, respectively;P< 0.001) and V82A/F/T (50% versus 81%, respectively;P= 0.05). HIV-1 isolates from 38 (49%) patients failing PI salvage therapy developed new primary PI resistance mutations including L90M, I84V, V82A, and G48V. Common combinations of primary and secondary PI resistance mutations after salvage therapy included mutations at amino acid positions 10, 82, and 46 and/or 54 in 16 patients; 10, 90, and 71 and/or 73 in 14 patients; 10, 73, 84, 90, and 46 and/or 54 in 5 patients; 10, 48, and 82 in 5 patients; and 30, 88 and 90 in 5 patients. In summary, during salvage PI therapy, most HIV-1 isolates with a single primary PI resistance mutation maintained their original mutations, and 49% developed additional primary PI resistance mutations. The persistence of L90M, V82A/F/T, G48V, and I84V during salvage therapy suggests that these mutations play a role in clinical resistance to multiple PIs.
Hemofiltrate CC Chemokine 1[9-74] Causes Effective Internalization of CCR5 and Is a Potent Inhibitor of R5-Tropic Human Immunodeficiency Virus Type 1 Strains in Primary T Cells and Macrophages
Authors: Münch Jan , Ständker Ludger , Pöhlmann Stefan , Baribaud Frédéric , Papkalla Armin , Rosorius Olaf , Stauber Roland , Sass Gabriele , Heveker Nikolaus , Adermann Knut , Escher Sylvia , Klüver Enno , Doms Robert W. , Forssmann Wolf-Georg , Kirchhoff Frank
Published: July 2002

Proteolytic processing of the abundant plasmatic human CC chemokine 1 (HCC-1) generates a truncated form, HCC-1[9-74], which is a potent agonist of CCR1, CCR3, and CCR5; promotes calcium influx and chemotaxis of T lymphoblasts, monocytes, and eosinophils; and inhibits infection by CCR5-tropic human immunodeficiency virus type 1 (HIV-1) isolates. In the present study we demonstrate that HCC-1[9-74] interacts with the second external loop of CCR5 and inhibits replication of CCR5-tropic HIV-1 strains in both primary T cells and monocyte-derived macrophages. Low concentrations of the chemokine, however, frequently enhanced the replication of CCR5-tropic HIV-1 isolates but not the replication of X4-tropic HIV-1 isolates. Only HCC-1[9-74] and HCC-1[10-74], but not other HCC-1 length variants, displayed potent anti-HIV-1 activities. Fluorescence-activated cell sorter analysis revealed that HCC-1[9-74] caused up to 75% down-regulation of CCR5 cell surface expression, whereas RANTES (regulated on activation, normal T-cell expressed and secreted) achieved a reduction of only about 40%. Studies performed with green fluorescent protein-tagged CCR5 confirmed that both HCC-1[9-74] and RANTES, but not full-length HCC-1, mediated specific internalization of the CCR5 HIV-1 entry cofactor. Our results demonstrate that the interaction with HCC-1[9-74] causes effective intracellular sequestration of CCR5, but they also indicate that the effect of HCC-1[9-74] on viral replication is subject to marked cell donor- and HIV-1 isolate-dependent variations.
Molecular Mechanisms of Fluconazole Resistance in
Candida dubliniensis
Isolates from Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis
Authors: Perea Sofia , López-Ribot José L. , Wickes Brian L. , Kirkpatrick William R. , Dib Olga P. , Bachmann Stefano P. , Keller Suzanne M. , Martinez Marcos , Patterson Thomas F.
Published: July 2002

Candida dubliniensis
is a newly identified species of
Candida
that is phenotypically similar to but genetically distinct from
C. albicans
. This organism has been recovered with increasing frequency from the oral cavities of human immunodeficiency virus (HIV)-infected and AIDS patients and has been implicated as a causative agent of oral candidiasis and systemic disease. In the present study we characterized the molecular mechanisms of resistance to fluconazole (FLC) in
C. dubliniensis
clinical isolates from two different HIV-infected patients with oropharyngeal candidiasis. Isolates were identified to the species level by phenotypic and genotypic tests. DNA-typing techniques were used to assess strain identity. Antifungal susceptibility testing was performed by NCCLS techniques. Northern blotting analysis was used to monitor the expression of genes encoding lanosterol demethylase (
ERG11
) and efflux transporters (
CDR
and
MDR1
) in matched sets of
C. dubliniensis
-susceptible and -resistant isolates by using probes generated from their homologous
C. albicans
sequences. In addition,
ERG11
genes were amplified by PCR, and their nucleotide sequences were determined in order to detect point mutations with a possible effect in the affinity for azoles. Decreasing susceptibilities to FLC were detected in
C. dubliniensis
isolates recovered from both patients during the course of treatment. FLC-resistant
C. dubliniensis
isolates from one patient demonstrated combined upregulation of the
MDR1
,
CDR1
, and
ERG11
genes. Among the isolates from the second patient, all isolates showing decreased susceptibility to FLC demonstrated upregulation of
MDR1
, whereas the levels of mRNA for the
ERG11
genes remained constant and the expression of
CDR
genes was negligible. Fourteen point mutations were found in the
ERG11
genes of the isolates with decreased susceptibility to FLC. These data demonstrate that the development of azole resistance in
C. dublinensis
clinical isolates from HIV-infected patients treated with FLC is mediated by multiple molecular mechanisms of resistance, similar to the observations found in the case of
C. albicans
.
Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293
Authors: Betz Ulrich A. K. , Fischer Rüdiger , Kleymann Gerald , Hendrix Martin , Rübsamen-Waigmann Helga
Published: July 2002

BAY 57-1293 belongs to a new class of antiviral compounds and inhibits replication of herpes simplex virus (HSV) type 1 and type 2 in the nanomolar range in vitro by abrogating the enzymatic activity of the viral primase-helicase complex. In various rodent models of HSV infection the antiviral activity of BAY 57-1293 in vivo was found to be superior compared to all compounds currently used to treat HSV infections. The compound shows profound antiviral activity in murine and rat lethal challenge models of disseminated herpes, in a murine zosteriform spread model of cutaneous disease, and in a murine ocular herpes model. It is active in parenteral, oral, and topical formulations. BAY 57-1293 continued to demonstrate efficacy when the onset of treatment was initiated after symptoms of herpetic disease were already apparent.