bluuebunny/crossref_metadata_2025 huggingface dataset:
Radio frequency-molecular beam epitaxial growth of InN epitaxial films on (0001) sapphire and their properties
Authors: Araki T. , Saito Y. , Yamaguchi T. , Kurouchi M. , Nanishi Y. , Naoi H.
Published: August 2004

Growth of InN by radio frequency plasma-excited molecular beam epitaxy on (0001) sapphire was systematically studied. To improve the crystalline quality of InN, the following growth conditions were found to be essential: (1) nitridation of sapphire, (2) two-step growth, (3) precise control of V/III ratio, and (4) selection of optimum growth temperature. Results of structural characterization using x-ray diffraction, transmission electron microscopy, and extended x-ray absorption fine structure have clearly demonstrated that InN grown in this study had single crystalline with ideal hexagonal wurtzite structure. It is confirmed, however, that the InN had a threading dislocation density on the order of 1010/cm2 and large twist distribution. Photoluminescence studies on these well-characterized InN clearly demonstrated that band-gap energy of InN should be less than 0.67 eV at room temperature.
Film properties of ALD HfO2 and La2O3 gate dielectrics grown on Si with various pre-deposition treatments
Authors: Triyoso D. H. , Hegde R. I. , Grant J. , Fejes P. , Liu R. , Roan D. , Ramon M. , Werho D. , Rai R. , La L. B. , Baker J. , Garza C. , Guenther T. , White B. E. , Tobin P. J.
Published: August 2004

In this article, we report film properties of HfO2 and La2O3 gate dielectrics grown on Si(100) substrate using atomic layer deposition (ALD) with various surfaces modified before film growth. The precursors used for HfO2 and La2O3 films are hafnium tetrachloride (HfCl4), lanthanum tris[bis(trimethylsilyl)amide] (C18H54N3LaSi6) and water. Pre-deposition treatments examined for HfO2 dielectric films include (1) surface nitridation using NH3, N2O, or NO, (2) substrate annealing in an oxidizing or reducing ambient, and (3) surface fluorination. These results were compared to those obtained using established approaches of growing HfO2 on an OH terminated surface produced chemically. Linear film growth was observed for the HfO2 with all pre-deposition treatments. Time-of-flight-secondary ion mass spectrometry (TOF-SIMS) and transmission electron microscopy (TEM) analysis indicated that all pre-treatments result in good film coverage with no interaction between HfO2 and silicon at the silicon substrate. The as deposited ALD HfO2 film is mainly amorphous, continuous, and relatively smooth on all pretreated Si surface. The thickness of a thin interfacial layer varies depending on the particular pre-treatments. Similar studies were also conducted for the growth of ALD La2O3. In this case, a significant interaction between La2O3 and silicon substrate was observed on films grown directly on chemical oxide. A rough interface between La2O3 and the silicon substrate is clearly seen in XTEM results. This interaction is more significant when the film is deposited at higher temperature. The XTEM images showed that the ALD La2O3 films are mostly amorphous. Results show that independent of surface pre-treatments, interactions between La2O3 and the silicon substrate occur for the deposition conditions explored here. Electrical characterization using evaporated platinum electrodes and mercury probe of the high-k film stacks have been carried out to determine the impact of the pre-treatments on the electrical properties of the films. Results indicated that ALD HfO2 films have higher dielectric constant, lower leakage and better flatband voltage stability during post deposition annealing compared to ALD La2O3 films. These results indicate that ALD HfO2 is a more promising candidate than ALD La2O3 due to superior thermal stability in contact with silicon.
Cation variations at semiconductor interfaces: ZnSe(001)/GaAs(001) superlattices
Authors: Farrell H. H. , LaViolette Randall A.
Published: August 2004

We investigated the possibility that the interface energy in heteroepitaxial compound semiconductor systems can be characterized by a unique value. We suggest that the per-bond binding energy, which is associated with the strength of the chemical bonds that span the interface between the different compounds, is this desired value. We chose the ZnSe(001)/GaAs(001) system for this study because of its relatively small lattice mismatch. Three chemically different interfaces were studied: One containing only Ga–Se bonds, one containing only Zn–As bonds, and one with an equal [i.e., 50:50] mixture of these bonds. We employed first-principles density-functional theory electronic-structure calculations to obtain the structure and binding energy of the bonds and these interfaces, for a variety of unit cells in order to find the favored configurations under static lattice conditions. The destabilizing effect of an interfacial charge imbalance, and, one of the limitations of density-functional theory calculations in this circumstance are also discussed.
Field emission characteristics of BN nanofilms grown on GaN substrates
Authors: Luo Haitao , Funakawa Shingo , Shen Wenzhong , Sugino Takashi
Published: August 2004

The field emission (FE) characteristics of boron nitride (BN) nanofilms grown on flat and roughened GaN substrates are investigated. A significant improvement is achieved by the BN nanocoating sample in contrast to a BN thick coating sample. In order to obtain a large field enhancement factor, H2 plasma treatment is employed to roughen the surface of GaN substrates. The roughened GaN substrates are demonstrated to be applicable to the BN nanofilms in further improving FE performance. An apparent enhancement is observed from the FE properties of BN nano/roughened GaN compared with those of BN nano/flat GaN and an optimum turn-on electric field of 3.2 V/μm is thus achieved.
Wet chemical cleaning of plasma oxide grown on heated (001) InP surfaces
Authors: Lita B. , Pluchery O. , Opila R. L. , Chabal Y. J. , Bunea G. , Holman J. P. , Bekos E. J.
Published: August 2004

Wet chemical cleaning is performed prior to most semiconductor processing steps, including epitaxial growth, metal and dielectric film deposition, and diffusion, with the purpose of removing unwanted chemical species that reside on the wafer surface. In this article we report the results of our investigations of a specific type of residue that is formed from the interaction between CF4/O2 plasmas and heated (001) InP surfaces. Our studies indicate that these residues are homogeneous oxides, about 10 nm thick, and that they impede wafer processing. In addition, these “plasma oxides” do not show significant growth after removal of the wafer from the plasma and storage in ambient. Moreover, we identify several aqueous solutions, such as HF and HNO3, that can be used to remove plasma residues at room temperature and likely induce regrowth of oxides similar to those found on “epi-ready”-like surfaces. In general, chemical cleaning in aqueous acidic solutions tends to stabilize the surface, with little further growth of oxide occurring in the hours following the wet chemical cleaning.
Structuring of GaAs. I. Chemical dry etching: Temperature and chlorine pressure dependence of etch rates
Authors: Dienelt Jens , von Sonntag Justus , Zimmer Klaus , Rauschenbach Bernd
Published: August 2004

Etch rates of chemical dry etching (CDE) of GaAs(100) were determined experimentally in the range from 220 to 475 K and dichlorine pressures up to 0.64×10−3 mbar. Model-based understanding of the CDE process is proposed to close the gap between experimental data derived from different setups. With the aid of pseudospecies and carefully selected simplifications all experimental features can be quantitatively explained. The thermal desorption kinetics of dichlorine from the GaAs(100) surface was derived successfully from etch rate data. This model paves the road for an extension to include the ion beam impact influence found in chemically assisted ion beam etching.
Microstructural defects in metalorganic vapor phase epitaxy of relaxed, graded InGaP: Branch defect origins and engineering
Authors: McGill L. M. , Fitzgerald E. A. , Kim A. Y. , Huang J.-W. , Yi S. S. , Grillot P. N. , Stockman S. A.
Published: August 2004

Strain-relaxed, compositionally graded InGaP layers grown by atmospheric-pressure metalorganic vapor phase epitaxy (APMOVPE) have previously been found to exhibit unusual contrast in transmission electron microscopy (TEM). The features that generate this contrast were termed “branch defects.” Branch defects have been shown to pin threading dislocations and are thus undesirable features for the realization of low dislocation density semiconductors. In this study, we compare the properties of branch defects formed during optimized, relaxed, graded InGaP buffer deposition in two different reactor configurations: a commercial, multiwafer, low-pressure reactor and a custom-built, atmospheric-pressure research reactor. Branch defect formation is further characterized via the introduction of in situ annealing interruptions during graded buffer deposition in the atmospheric-pressure system. Branch defects are observed in material from both reactor systems, suggesting that they are a phenomenon intrinsic to InGaP graded buffer growth. Careful TEM studies of the resulting samples reveal that the phase space for the formation of branch defects is similar in both reactor configurations. During standard optimized graded buffer growth, higher growth temperatures delay the onset of branch defect formation to higher indium fractions in the graded buffer. Low growth temperatures produce branch defects at lower indium fractions, and these defects tend to be more closely spaced. In addition, the formation of branch defects is favored by low V/III ratios and in situ growth interruption and annealing. Annealing is found to create anisotropic strain relaxation in the graded buffer, which we attribute to the blocking of gliding threading dislocations by preferentially oriented branch defects. Based on the observed properties of branch defects and the factors that affect their formation, it appears that these defects are a manifestation of local variations in indium concentration that develop on the sample surface during MOVPE and are buried in the bulk due to kinetic limitations.
Effect of electrostatic discharge on power output and reliability of 850 nm vertical-cavity surface-emitting lasers
Authors: Huang Chun-Yuan , Wu Meng-Chyi , Yu Hsin-Chieh , Jiang Wen-Jang , Wang Jin-Mei , Sung Chia-Pin
Published: August 2004

In this article, we investigate the influence of electrostatic discharge (ESD) stress voltage on the device performance of 850 nm vertical-cavity surface-emitting lasers (VCSELs). The ESD effect induces dark-region defects, which act as nonradiative recombination centers in the active layer and increase the leakage current and degrade the light output power. Without ESD stress voltage, the VCSELs exhibit multiple transverse mode. However, the devices exhibit a weak but single fundamental mode with smaller beam divergence by increasing the stress voltage up to 2.6 kV. In addition, the VCSELs have serious degradation in light output power and a lifetime of less than 5 h at stress voltage beyond the ESD threshold voltage of 1.2 kV.
Chemical vapor deposition–physical vapor deposition aluminum plug process for dynamic random-access memory applications
Authors: Lee Won-Jun , Rha Sa-Kyun
Published: August 2004

The integrated chemical vapor deposition (CVD)–physical vapor deposition (PVD) Al plug process was successfully applied to capacitor-over-bit-line-type dynamic random-access memory process flow for the simultaneous formation of plugs and wires. The CVD-PVD Al film completely filled re-entrant vias with aspect ratios up to 10:1, and Al plugs showed lower via resistance compared with that of conventional W plugs. The PVD Al temperature can be as low as 350 °C, which is compatible with most low-dielectric-constant intermetal dielectric materials. However, outgassing from the intermetal dielectric was critical to complete via filling of the CVD-PVD Al film, and the conventional degassing process was insufficient for eliminating outgassing from hydrogen silsesquioxane. Sufficient baking after the via etching was effective for eliminating outgassing, and complete via filling was achieved.
Self-assembling growth of (Ba,Sr)TiO3 epitaxial thin films
Authors: Li Yanrong , Li Jinlong , Zhang Ying , Deng Xinwu , Liu Xingzhao , Tao Bowan
Published: August 2004

Ferroelectric thin films of SrTiO3, BaTiO3, and (Ba,Sr)TiO3 were fabricated epitaxially on SrTiO3(100) and Si(111) single crystal substrates in an ultrahigh vacuum (10−5 Pa) by laser molecular beam epitaxy. The lowest crystallization temperatures of homoepitaxial thin films of SrTiO3 and heteroepitaxial thin films of BaTiO3 and (Ba,Sr)TiO3 on SrTiO3(100) substrates obtained were as low as 280, 330, and 340 °C, respectively. With the growth rate lower than 0.17 Å/s, it was discovered that the thickness of each layer of BTO film was an integral of the BTO unit cell height. When the growth rate was decreased from 0.17 to 0.05 Å/s, the thickness of each layer varied from nine unit cells to one unit cell. It is very important to construct a nanometer structure of inorganic ABO3 perovskite oxides by this kind of self-assembly.
On the formation mechanism of epitaxial Ge islands on partially relaxed SiGe buffer layers
Authors: Kim H. J. , Liu J. , Zhao Z. M. , Xie Y. H.
Published: August 2004

We describe the morphological evolution of Ge epitaxial films grown on partially relaxed SiGe buffer layers. Three different types of surface sites exist on the buffer layer surface when the spacing between the buried dislocations is significantly larger than the surface diffusion length of Ge adatoms. The three types of nucleation sites include those over dislocation intersections, those over single dislocation lines, and those far away from dislocations. Epitaxial growth of Ge on such a relaxed buffer under near equilibrium condition exhibits three-stage nucleation and growth of Ge islands, also known as self-assembled quantum dots (SAQD). Denuded zones exist next to the buried dislocation lines. The temperature dependence of the denuded zone width together with the average spacing between SAQDs provides sufficient information for determining both the activation energy and the pre-exponential factor of surface diffusion of Ge adatoms. SAQDs located at the three sites are strained differently as indicated by the distinct difference in the critical dot size for pyramid-to-dome transition. The experimental observation can be explained by assuming the energy barrier for the surface diffusion of Ge adatoms increases with decreasing misfit strain as predicted by theory [van de Walle et al., Phys Rev. B 67, R41308 (2003)]. Calculations of Ge adatom concentration profile based on Fick’s second law of diffusion does predict the presence of denuded zones with their widths being dependent on the diffusion coefficient; i.e., on the substrate temperature. The observed morphological evolution of Ge epitaxial films supports Ge island nucleation and growth as the SAQD formation mechanism as opposed to strain-induced surface instability.
Growth of single crystalline GaN thin films on Si(111) substrates by high vacuum metalorganic chemical vapor deposition using a single molecular precursor
Authors: Lee Sang Hun , Boo Jin-Hyo , Lee Sung Yong , Yoo Seung Ho , Kim Chang Gyoun , Lee Young Kuk , Kim Yunsoo
Published: August 2004

Hexagonal GaN thin films were grown on Si(111) substrates using single molecular precursor by high vacuum metalorganic chemical vapor deposition at various temperatures from 600 to 800 °C and pressures in the range of 2×10−6 to 2×10−5 Torr. We first developed and synthesized the single molecular precursor of diethylazidogallium methylhydrazine adduct, [(Et)2Ga(N3)HzMe], with the objectives of reducing carbon content in the GaN films and lowering growth temperatures. Results of x-ray diffraction (XRD), x-ray pole figure, and x-ray photoelectron spectroscopy measurements showed that this approach yielded a single crystalline GaN thin film of [0002] orientation with relatively low carbon content. Ga-rich compositions Ga:N of 1:0.92 were obtained at a temperature of 750 °C and a pressure of 2×10−6 Torr. However, for growth temperatures below 700 °C, we found the films to be polycrystalline. Scanning electron microscope (SEM) and atomic force microscope (AFM) images showed that the as-grown GaN films have a smooth surface morphology. Based on XRD, AFM, and SEM results, we identified effects of deposition temperature and pressure on the growth rate and crystallinity, and can suggest that our deposition process is governed by diffusion rate control. Optical properties were investigated by photoluminescence, which revealed an emission peak at 3.40 eV with a full width at half-maximum of approximately 100 meV for a GaN film grown at 750 °C and 2×10−6 Torr.
Resonant tunneling behavior and discrete dopant effects in narrow ultrashort ballistic silicon-on-insulator metal-oxide-semiconductor field-effect transistors
Authors: Gilbert M. J. , Ferry D. K.
Published: August 2004

We utilize an efficient, fully quantum mechanical approach to calculating ballistic transport in a fully depleted, silicon-on-insulator metal-oxide-semiconductor field-effect transistor in three dimensions to examine realistic devices with quantum wire channels. We find that, by including the atomistic nature of these small devices in the simulation, we observe variations in the threshold voltage dependent on the position of the dopants in the channel. Further, we find that the narrow channel access geometry creates a situation in which the impinging electron density in the source undergoes resonant tunneling in order to reach the drain end of the device.
Correlation between interface structure and light emission at 1.3–1.55 μm of (Ga,In)(N,As) diluted nitride heterostructures on GaAs substrates
Authors: Trampert Achim , Chauveau Jean-Michel , Ploog Klaus H. , Tournié Eric , Guzmán Alvaro
Published: August 2004

We have investigated by transmission electron microscopy and photoluminescence spectroscopy the impact of the structural features on the optical properties of (Ga,In)(N,As) quantum wells emitting in the 1.3 to 1.55 μm wavelength range. Our electron microscopy analysis demonstrates morphological instabilities in the (Ga,In)(N,As) layers with high In and N concentrations. We show that the optical properties are strongly influenced by the actual microstructure (interface roughness, composition variations). High photoluminescence efficiency is only achieved for quantum wells grown in the two-dimensional mode. Ex situ annealing of those perfect quantum well structures can still improve their luminescence, and the concomitant structural changes are detected as local rearrangements of N and In atoms inside the well.
Size selection of oxidized GaN crystallites and their cathodoluminescence properties
Authors: Akiyama Miwako , Egawa Shinichi , Matsukawa Kohji , Honda Tohru , Kawanishi Hideo
Published: August 2004

GaN particles of different sizes were separated by a sedimentation technique. We find that a correlation exists between the cathodoluminescence (CL) spectra of the particles and their average sizes. These results imply that the particles contain a substantial fraction of GaN nanocrystallites (NCs) whose emission is shifted by quantum size effects and whose proportions differ with the overall size of the particle. X-ray photoelectron spectroscopy data combined with ion etching show that the NCs comprising these clusters have a GaN core surrounded by a gallium oxide shell. The results indicate that size-separated GaN particles may be useful CL sources of light for exciting phosphors over a range of UV wavelengths without the need for alloys such as AlGaInN.
High field transport in GaN/AlGaN heterostructures
Authors: Barker J. M. , Ferry D. K. , Goodnick S. M. , Koleske D. D. , Allerman A. , Shul R. J.
Published: August 2004

Experimental as well as theoretical studies have been performed on the velocity-field characteristics of AlGaN/GaN heterostructures. A comparison of these studies shows that the experimental velocities are comparable to those expected from previously published simulations based upon Monte Carlo techniques. Several possible mechanisms for the low value of the velocity previously found are discussed, including nonequilibrium phonons and local inhomogeneities in the field.
Fundamental reactions controlling anion exchange during the synthesis of Sb/As mixed-anion heterojunctions
Authors: Brown April S. , Losurdo Maria , Bruno Giovanni , Brown Terence , May Gary
Published: August 2004

As/Sb and Sb/As anion exchange reactions are characterized and modeled in order to better understand and control mixed-anion heterojunction synthesis by molecular-beam epitaxy. The importance of substrate temperature, anion flux exposure time, and incident anion molecular species is examined. Sb/As structures exhibit Sb surface segregation, and the subsequent incorporation of the segregating surface population into epitaxial overlayers. As/Sb exchange is significant in extent of the reaction, and enhanced with incident dimer fluxes. Competitive reactions between exchange and isoelectronic compound formation yield complex structures.
Improved surface morphology in GaN homoepitaxy by NH3-source molecular-beam epitaxy
Authors: Koida T. , Uchinuma Y. , Kikuchi J. , Wang K. R. , Terazaki M. , Onuma T. , Keading J. F. , Sharma R. , Nakamura S. , Chichibu S. F.
Published: August 2004

GaN homoepitaxial layers of improved surface morphology were obtained by a NH3-source molecular-beam epitaxy method supplying a proper reactive NH3-to-Ga flux ratio (V/III ratio) on the growing surface, combined with a procedure to prevent the surface roughening of the GaN/(0001) Al2O3 epitaxial templates, which were prepared by metalorganic vapor-phase epitaxy. In situ monitoring on the heated templates revealed their thermal decomposition above 700 °C in ultrahigh vacuum, which gave rise to surface unevenness of both initially atomically flat templates and the homoepitaxial layers. The surface flatness was maintained by depositing the “flux-modulated” GaN prior to the high-temperature growth, where Ga flux was supplied intermittently during heating the template under continuous NH3 flow. The increase in V/III ratio greatly improved the surface flatness. As a result of the epilayer/template interface control and growth optimization, the epilayers exhibited higher mobility, smaller full width at half-maximum value (34 meV) of excitonic photoluminescence (PL) peak, and longer PL lifetime of 180 ps at 293 K.
Thickness dependence of structural and electrical characteristics of ZrO2 thin films as grown on Si by chemical-vapor deposition
Authors: Huang Shih-Sian , Wu Tai-Bor
Published: August 2004

Microstructural and electrical characteristics of as grown ZrO2 thin films having different thicknesses of 1.2–10 nm were investigated. The films were grown on a p-Si substrate by chemical-vapor deposition at 275 °C using zirconium t-butoxide as the precursor. The structural characterization showed that the ZrO2 films had a microstructure that changed from amorphous to polycrystalline with increased film thickness over 3.2 nm, along with a SiOx interfacial layer ∼1.5 nm thick, irrespective of the film thickness. From the hysteresis in the capacitance–voltage (C–V) relation of the Al/ZrO2/SiOx/p-Si metal–oxide–semiconductor capacitors, it was found that the density of the oxide-trapped charge drastically increased from 2.22×1010 to 3.54×1012 cm−2 as the films change from amorphous to polycrystalline. Furthermore, the shift of flatband voltage in the C–V curves revealed that the fixed charges changed sign from negative to positive. An increase of interface-state density was also found from the stretch-out of the C–V curves and the increase of turnaround voltage in the current–voltage (I–V) relation. In addition, an analysis of the I–V relation indicated that the negatively biased leakage current in the ultrathin stacked dielectrics followed the direct tunneling of holes from substrate to gate before hard breakdown. However, for the thicker films, the leakage current changed to Fowler–Nordheim tunneling of electrons from the gate to the substrate.
Genotype and Phenotype Patterns of Human Immunodeficiency Virus Type 1 Resistance to Enfuvirtide during Long-Term Treatment
Authors: Menzo Stefano , Castagna Antonella , Monachetti Alessia , Hasson Hamid , Danise Anna , Carini Elisabetta , Bagnarelli Patrizia , Lazzarin Adriano , Clementi Massimo
Published: August 2004

The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC
50
s) ranging from 0.6 to 12.8 μg/ml, whereas the IC
50
for isolates with baseline sequences was 0.013 ± 0.010 μg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.
De Novo Design of Potent Antimicrobial Peptides
Authors: Frecer V. , Ho B. , Ding J. L.
Published: August 2004

Lipopolysaccharide (LPS), shed by gram-negative bacteria during infection and antimicrobial therapy, may lead to lethal endotoxic shock syndrome. A rational design strategy based on the presumed mechanism of antibacterial effect was adopted to design cationic antimicrobial peptides capable of binding to LPS through tandemly repeated sequences of alternating cationic and nonpolar residues. The peptides were designed to achieve enhanced antimicrobial potency due to initial bacterial membrane binding with a reduced risk of endotoxic shock. The peptides designed displayed binding affinities to LPS and lipid A (LA) in the low micromolar range and by molecular modeling were predicted to form amphipathic β-hairpin-like structures when they bind to LPS or LA. They also exhibited strong effects against gram-negative bacteria, with MICs in the nanomolar range, and low cytotoxic and hemolytic activities at concentrations significantly exceeding their MICs. Quantitative structure-activity relationship (QSAR) analysis of peptide sequences and their antimicrobial, cytotoxic, and hemolytic activities revealed that site-directed substitutions of residues in the hydrophobic face of the amphipathic peptides with less lipophilic residues selectively decrease the hemolytic effect without significantly affecting the antimicrobial or cytotoxic activity. On the other hand, the antimicrobial effect can be enhanced by substitutions in the polar face with more polar residues, which increase the amphipathicity of the peptide. On the basis of the QSARs, new analogs that have strong antimicrobial effects but that lack hemolytic activity can be proposed. The findings highlight the importance of peptide amphipathicity and allow a rational method that can be used to dissociate the antimicrobial and hemolytic effects of cationic peptides, which have potent antimicrobial properties, to be proposed.
Impact of Alpha Interferon and Ribavirin on the Function of Maturing Dendritic Cells
Authors: Barnes Eleanor , Salio Mariolina , Cerundolo Vincenzo , Medlin Joanne , Murphy Shona , Dusheiko Geoffrey , Klenerman Paul
Published: August 2004

Alpha interferon and ribavirin are required in combination to achieve a sustained virological response in the treatment of hepatitis C virus (HCV) infection. Alpha interferon has direct antiviral activity and also enhances HCV-specific T-cell responses. Ribavirin has little direct activity against HCV but reduces hepatic inflammation. It is therefore likely that these drugs in combination have hitherto unidentified immunological effects. In the present study we investigated the effects of alpha interferon and ribavirin on dendritic cell (DC) maturation and cytokine production induced by double-stranded RNA in vitro. Alpha interferon alone enhanced the expression of HLA class I, HLA class II, and CD86 on immature DCs but did not stimulate full DC maturation, which requires the expression of CD83. Alpha interferon enhanced the production of interleukin 12 p70 [IL-12(p70)] and tumor necrosis factor alpha (TNF-α) but had no effect on IL-10 production. In contrast, ribavirin at physiological doses had no effect on DC maturation but markedly suppressed the production of TNF-α, IL-10, and IL-12(p70). The suppression of cytokines by ribavirin cannot be explained by the induction of DC apoptosis or cell death. Quantitative PCR confirmed that cytokine suppression occurs at the level of mRNA. The suppression of IL-12(p70) and TNF-α in maturing DCs may explain the reduction in hepatic inflammation observed during ribavirin monotherapy. Combination alpha interferon-ribavirin therapy may alter the cytokine profile of maturing DCs overall by suppressing IL-10 production but maintaining IL-12(p70) and TNF-α production, a pattern that would favor viral elimination through downstream effects on T cells.
Paradoxical Effect of Caspofungin: Reduced Activity against
Candida albicans
at High Drug Concentrations
Authors: Stevens David A. , Espiritu Marife , Parmar Rachana
Published: August 2004

Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare. We noted paradoxical turbid growth of
Candida albicans
isolates in broth in some high (supra-MIC) concentrations. Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 μg/ml, the frequency was 16%. Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls. Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series. Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent. Among a selected series of isolates tested at concentrations up to 50 μg/ml, an additional 53% showed a “mini-paradoxical effect”: no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration). These effects were reproducible; medium dependent in extent; noted in macro- and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other
Candida
species; and not due to destruction of drug in tubes showing the effect. Cooperative enhancement of inhibition by a second drug could eradicate the effect. We postulate that high drug concentrations derepress or activate resistance mechanisms. The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences.
Incidence of Antibiotic Resistance inCampylobacter jejuniIsolated in Alberta, Canada, from 1999 to 2002, with Special Reference totet(O)-Mediated Tetracycline Resistance
Authors: Gibreel Amera , Tracz Dobryan M. , Nonaka Lisa , Ngo Trinh M. , Connell Sean R. , Taylor Diane E.
Published: August 2004

Of 203 human clinical isolates ofCampylobacter jejunifrom Alberta, Canada (1999 to 2002), 101 isolates (50%) were resistant to at least 64 μg of tetracycline/ml, with four isolates exhibiting higher levels of tetracycline resistance (512 μg/ml). In total, the MICs for 37% of tetracycline-resistant isolates (256 to 512 μg/ml) were higher than those previously reported inC. jejuni(64 to 128 μg/ml). In the tetracycline-resistant clinical isolates, 67% contained plasmids and all contained thetet(O) gene. Four isolates resistant to high levels of tetracycline (MIC = 512 μg/ml) contained plasmids carrying thetet(O) gene, which could be transferred to other isolates ofC. jejuni. The tetracycline MICs for transconjugants were comparable to those of the donors. Cloning oftet(O) from the four high-level tetracycline-resistant isolates conferred an MIC of 32 μg/ml forEscherichia coliDH5α. In contrast, transfer to a strain ofC. jejuniby using mobilization conferred an MIC of 128 μg/ml. DNA sequence analysis determined that thetet(O) genes encoding lower MICs (64 to 128 μg/ml) were identical to one other, although thetet(O) genes encoding a 512-μg/ml MIC demonstrated several nucleotide substitutions. The quinolone resistance determining region of four ciprofloxacin-resistant isolates (2%) was analyzed, and resistance was associated with a chromosomal mutation in thegyrAgene resulting in a Thr-86-Ile substitution. In addition, six kanamycin-resistant isolates contained large plasmids that carry theaphA-3marker coding for 3′-aminoglycoside phosphotransferase. Resistance to erythromycin was not detected in 203 isolates. In general, resistance to most antibiotics inC. jejuniremains low, except for resistance to tetracycline, which has increased from about 8 to 50% over the past 20 years.
Levofloxacin-Resistant Invasive
Streptococcus pneumoniae
in the United States: Evidence for Clonal Spread and the Impact of Conjugate Pneumococcal Vaccine
Authors: Pletz Mathias W. R. , McGee Lesley , Jorgensen James , Beall Bernard , Facklam Richard R. , Whitney Cynthia G. , Klugman Keith P.
Published: August 2004

The emergence of fluoroquinolone resistance in sterile-site isolates of
Streptococcus pneumoniae
is documented in this study characterizing all invasive levofloxacin-resistant (MIC, ≥8 mg/liter)
S. pneumoniae
isolates (
n
= 50) obtained from the Centers for Disease Control and Prevention Active Bacterial Core Surveillance from 1998 to 2002. Resistance among all isolates increased from 0.1% in 1998 to 0.6% in 2001 (
P
= 0.008) but decreased to 0.4% in 2002, while resistance among vaccine serotypes continued to increase from 0.3% in 1998 to 1.0% in 2002, suggesting that fluoroquinolones continue to exert selective pressure on these vaccine serotypes. Only 22% of resistant isolates were not covered by the conjugate vaccine serogroups. Multilocus sequence typing revealed that 58% of resistant strains were related to five international clones identified by the Pneumococcal Molecular Epidemiology Network, with the Spain
23F
-1 clone being most frequent (16% of all isolates). Thirty-six percent of the isolates were coresistant to penicillin, 44% were coresistant to macrolides, and 28% were multiresistant to penicillin, macrolides, and fluoroquinolones. Fifty percent of the isolates were resistant to any three drug classes. Ninety-four percent of the isolates had multiple mutations in the quinolone resistance-determining regions of the
gyrA
,
gyrB
,
parC
, and
parE
genes. In 16% of the isolates, there was evidence of an active efflux mechanism. An unusual isolate was found that showed only a single
parE
mutation and for which the ciprofloxacin MIC was lower (2 mg/liter) than that of levofloxacin (8 mg/liter). Our results suggest that invasive pneumococcal isolates resistant to levofloxacin in the United States show considerable evidence of multiple resistance and of clonal spread.
Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin
Authors: Conte John E. , Golden Jeffrey A. , Kipps Juliana , Zurlinden Elisabeth
Published: August 2004

The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods.Cmax/90% minimum inhibitory concentration (MIC90) ratios, area under the concentration-time curve (AUC)/MIC90ratios, intrapulmonary drug exposure ratios, and percent time above MIC90during the dosing interval (%T> MIC90) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, theCmax(mean ± standard deviations), AUC0-24, and half-life for plasma were 0.181 ± 0.084 μg/ml, 0.902 ± 0.469 μg · h/ml, and 4.85 ± 1.10 h, respectively; for ELF the values were 0.9 ± 0.2 μg/ml, 11.4 μg · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ± 6.4 μg/ml, 160.8 μg · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, theCmax(mean ± standard deviations), AUC0-24, and half-life for plasma were 0.500 ± 0.168 μg/ml, 3.067 ± 1.205 μg · h/ml, and 4.94 ± 0.66 h, respectively; for ELF the values were 2.7 ± 2.0 μg/ml, 24.15 μg · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ± 38.7 μg/ml, 636.2 μg · h/ml, and 11.6 h, respectively. We concluded that theCmax/MIC90ratios, AUC/MIC90ratios, %T> MIC90values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.
Terbinafine Resistance Mediated by Salicylate 1-Monooxygenase inAspergillus nidulans
Authors: Graminha Marcia A. S. , Rocha Eleusa M. F. , Prade Rolf A. , Martinez-Rossi Nilce M.
Published: August 2004

Resistance to antifungal agents is a recurring and growing problem among patients with systemic fungal infections. UV-inducedAspergillus nidulansmutants resistant to terbinafine have been identified, and we report here the characterization of one such gene. A sib-selected, 6.6-kb genomic DNA fragment encodes a salicylate 1-monooxygenase (salA), and a fatty acid synthase subunit (fasC) confers terbinafine resistance upon transformation of a sensitive strain. Subfragments carryingsalAbut notfasCconfer terbinafine resistance.salAis present as a single-copy gene on chromosome VI and encodes a protein of 473 amino acids that is homologous to salicylate 1-monooxygenase, a well-characterized naphthalene-degrading enzyme in bacteria.salAtranscript accumulation analysis showed terbinafine-dependent induction in the wild type and the UV-induced mutant Terb7, as well as overexpression in a strain containing thesalAsubgenomic DNA fragment, probably due to the multicopy effect caused by the transformation event. Additional naphthalene degradation enzyme-coding genes are present in fungal genomes, suggesting that resistance could follow degradation of the naphthalene ring contained in terbinafine.
β-Lactamase-Producing Nontypeable
Haemophilus influenzae
Fails To Protect
Streptococcus pneumoniae
from Amoxicillin during Experimental Acute Otitis Media
Authors: Westman Eva , Lundin Susanne , Hermansson Ann , Melhus Åsa
Published: August 2004

Acute otitis media (AOM) is the most common reason for outpatient antimicrobial therapy. Mixed infections pose a potential problem, since the first-line drug used for the treatment of AOM, amoxicillin, can be neutralized by β-lactamase-producing pathogens of the upper respiratory tract. To study the effects of a 5-day course of amoxicillin on a mixed middle ear infection, rats were challenged with
Streptococcus pneumoniae
alone or in combination with β-lactamase-producing nontypeable
Haemophilus influenzae
. Amoxicillin was introduced at the clinical peak of the infection. Local and systemic changes were monitored by otomicroscopy, bacterial culture, and analysis of histological changes and the expression of the transforming growth factor beta (TGF-β) gene. β-Lactamase-producing
H. influenzae
did not demonstrate an ability to protect
S. pneumoniae
. Amoxicillin eradicated the pneumococci in all treated animals but increased to some degree the ability of
H. influenzae
to persist at the site of infection. Thus, only an insignificant acceleration of the resolution of the AOM caused by a mixture of pathogens was observed during treatment. Moderate to major morphological changes could not be avoided by treatment of the mixed infections, but a slight downregulation of TGF-β expression was observed. In contrast to infections caused by a single pathogen, the mixed infections induced white plaques in the tympanic membrane at a remarkably high frequency independent of treatment. These experimental findings constitute support for further studies of antimicrobial drugs and AOM caused by bacteria with and without mechanisms of antibiotic resistance.
Impact of Nelfinavir Resistance Mutations on In Vitro Phenotype, Fitness, and Replication Capacity of Human Immunodeficiency Virus Type 1 with Subtype B and C Proteases
Authors: Gonzalez Luis M. F. , Brindeiro Rodrigo M. , Aguiar Renato S. , Pereira Helena S. , Abreu Celina M. , Soares Marcelo A. , Tanuri Amilcar
Published: August 2004

Human immunodeficiency virus type 1 subtype B and C proteases were manipulated to contain 90M, 88D, or 89L, and their in vitro biological properties were studied. We showed that D30N has significantly more impact in subtype C than in subtype B counterparts, accounting for the reported low prevalence of this mutation in patients failing nelfinavir-based regimens.
Quinolone-Resistant
Haemophilus influenzae
in a Long-Term-Care Facility: Nucleotide Sequence Characterization of Alterations in the Genes Encoding DNA Gyrase and DNA Topoisomerase IV
Authors: Li Xinying , Mariano Noriel , Rahal James J. , Urban Carl M. , Drlica Karl
Published: August 2004

Fluoroquinolone-resistant isolates of
Haemophilus influenzae,
obtained from a long-term care facility, were examined for nucleotide sequence differences in the quinolone-resistance-determining regions of
gyrA, gyrB, parC
, and
parE
. Similarities among the resistant isolates, plus multiple differences with susceptible isolates, suggest clonal dissemination involving two resistant subclones.
Lack of Association between Hypermutation and Antibiotic Resistance Development inPseudomonas aeruginosaIsolates from Intensive Care Unit Patients
Authors: Gutiérrez Olivia , Juan Carlos , Pérez José L. , Oliver Antonio
Published: August 2004

Hypermutation is a common feature ofPseudomonas aeruginosaisolates from chronically infected cystic fibrosis patients that is linked with antibiotic resistance development. In this work, using a large collection of sequentialP. aeruginosaisolates from ICU patients, we found that despite the fact that mutational antibiotic resistance development is a frequent outcome, the prevalence of hypermutable strains is low (found in isolates from only 1 of 103 patients) and there is no evidence of coselection of the hypermutable and antibiotic resistance phenotypes.
Genetic and Culture-Based Approaches for Detecting Macrolide Resistance inChlamydia pneumoniae
Authors: Riska Paul F. , Kutlin Andrei , Ajiboye Patrick , Cua Arnold , Roblin Patricia M. , Hammerschlag Margaret R.
Published: August 2004

Three clinicalChlamydia pneumoniaeisolates for which the MIC of azithromycin increased after treatment were investigated for genetic evidence of macrolide resistance. Attempts to induce antibiotic resistance in vitro were made. No genetic mechanism was identified for the phenotypic change in theseC. pneumoniaeisolates. No macrolide resistance was obtained in vitro.
Combination Therapy Using Sodium Antimony Gluconate in Stearylamine-Bearing Liposomes against Established and ChronicLeishmania donovaniInfection in BALB/c Mice
Authors: Pal Swati , Ravindran Rajesh , Ali Nahid
Published: August 2004

In this work we report the activity seen with combination therapy using sodium antimony gluconate in liposomes composed of egg phosphatidyl choline and stearylamine for elimination ofLeishmania donovaniparasites from the liver and spleen of BALB/c mice with established and chronic infections.
Activities of Dicationic Compounds against
Trichomonas vaginalis
Authors: Crowell Andrea L. , Stephens Chad E. , Kumar Arvind , Boykin David W. , Secor W. Evan
Published: August 2004

We evaluated 44 novel cationic compounds for activity against metronidazole-sensitive and -resistant
Trichomonas vaginalis
isolates. Six compounds in three different structural classes demonstrated 50% inhibitory concentrations as low as 1 μM against both sensitive and resistant isolates, suggesting a mode of action independent of parasite biochemical pathways that confer resistance to 5-nitroimidazoles.
The AcrAB-TolC Pump Is Involved in Macrolide Resistance but Not in Telithromycin Efflux inEnterobacter aerogenesandEscherichia coli
Authors: Chollet Renaud , Chevalier Jacqueline , Bryskier André , Pagès Jean-Marie
Published: August 2004

The role of the AcrAB-TolC pump in macrolide and ketolide susceptibility inEscherichia coliandEnterobacter aerogeneswas studied. Efflux pump inhibitor restored erythromycin, clarithromycin, and telithromycin susceptibilities to multidrug-resistant isolates. No modification of telithromycin accumulation was detected inE. aerogenes acrABortolCderivatives compared to that in the parental strain. Two independent efflux pumps, inhibited by phenylalanine arginine β-naphthylamide, expel macrolides and telithromycin inE. aerogenes.
GAIN DEGRADATION AND ENHANCED LOW-DOSE-RATE SENSITIVITY IN BIPOLAR JUNCTION TRANSISTORS
Authors: SCHRIMPF R. D.
Published: August 2004

The current gain of irradiated bipolar junction transistors decreases due to increased recombination current in the emitter-base depletion region and the neutral base. This recombination current depends on the interaction of two factors: (1) decreased minority-carrier lifetime at the Si / SiO 2 interface or in the bulk Si and (2) changes in surface potential caused by charge in the oxide. In npn transistors, these two factors both result in increased base current, while in pnp devices, positive charge in the oxide moderates the increase in base current due to surface recombination. In some technologies, the amount of degradation that occurs at a given total dose increases as the dose rate decreases. This enhanced low-dose-rate sensitivity results from space-charge effects produced by slowly transporting holes and protons in the oxide that covers the emitterbase junction.
A STUDY ON A TWO UNIT STANDBY SYSTEM WITH ERLANGIAN REPAIR TIME
Authors: CHANDRASEKHAR P. , NATARAJAN R. , YADAVALLI V. S. S.
Published: August 2004

A two-unit cold standby system is considered. The failure rate of a unit is a constant and the repair time distribution is a two-stage Erlang distribution. Measures of system performance such as reliability, mean time before failure, system availability, and steady-state availability are derived. Also, a consistent asymptotically normal estimator and a 100(1-α)% asymptotic confidence interval for the steady-state availability of the system are obtained.