bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Basis of Resistance to Macrolides and Other Antibiotics in Commensal Viridans Group Streptococci and
Gemella
spp. and Transfer of Resistance Genes to
Streptococcus pneumoniae
Authors: Cerdá Zolezzi Paula , Laplana Leticia Millán , Calvo Carmen Rubio , Cepero Pilar Goñi , Erazo Melisa Canales , Gómez-Lus Rafael
Published: August 2004

We assessed the mechanisms of resistance to macrolide-lincosamide-streptogramin B (MLS
B
) antibiotics and related antibiotics in erythromycin-resistant viridans group streptococci (
n
= 164) and
Gemella
spp. (
n
= 28). The macrolide resistance phenotype was predominant (59.38%); all isolates with this phenotype carried the
mef
(A) or
mef
(E) gene, with
mef
(E) being predominant (95.36%). The
erm
(B) gene was always detected in strains with constitutive and inducible MLS
B
resistance and was combined with the
mef
(A/E) gene in 47.44% of isolates. None of the isolates carried the
erm
(A) subclass
erm
(TR),
erm
(A), or
erm
(C) genes. The
mel
gene was detected in all but four strains carrying the
mef
(A/E) gene. The
tet
(M) gene was found in 86.90% of tetracycline-resistant isolates and was strongly associated with the presence of the
erm
(B) gene. The

cat
pC194

gene was detected in seven chloramphenicol-resistant
Streptococcus mitis
isolates, and the
aph
(
3′
)-
III
gene was detected in four viridans group streptococcal isolates with high-level kanamycin resistance. The
intTn
gene was found in all isolates with the
erm
(B),
tet
(M),
aph
(
3′
)
-III
, and

cat
pC194

gene. The
mef
(E) and
mel
genes were successfully transferred from both groups of bacteria to
Streptococcus pneumoniae
R6 by transformation. Viridans group streptococci and
Gemella
spp. seem to be important reservoirs of resistance genes.
Cloning, Sequencing, and Functional Analysis of an Iterative Type I Polyketide Synthase Gene Cluster for Biosynthesis of the Antitumor Chlorinated Polyenone Neocarzilin in “
Streptomyces carzinostaticus
”
Authors: Otsuka Miyuki , Ichinose Koji , Fujii Isao , Ebizuka Yutaka
Published: August 2004

Neocarzilins (NCZs) are antitumor chlorinated polyenones produced by “
Streptomyces carzinostaticus
” var. F-41. The gene cluster responsible for the biosynthesis of NCZs was cloned and characterized. DNA sequence analysis of a 33-kb region revealed a cluster of 14 open reading frames (ORFs), three of which (ORF4, ORF5, and ORF6) encode type I polyketide synthase (PKS), which consists of four modules. Unusual features of the modular organization is the lack of an obvious acyltransferase domain on modules 2 and 4 and the presence of longer interdomain regions more than 200 amino acids in length on each module. Involvement of the PKS genes in NCZ biosynthesis was demonstrated by heterologous expression of the cluster in
Streptomyces coelicolor
CH999, which produced the apparent NCZ biosynthetic intermediates dechloroneocarzillin A and dechloroneocarzilin B. Disruption of ORF5 resulted in a failure of NCZ production, providing further evidence that the cluster is essential for NCZ biosynthesis. Mechanistic consideration of NCZ formation indicates the iterative use of at least one module of the PKS, which subsequently releases its product by decarboxylation to generate an NCZ skeleton, possibly catalyzed by a type II thioesterase encoded by ORF7. This is a novel type I PKS system of bacterial origin for the biosynthesis of a reduced polyketide chain. Additionally, the protein encoded by ORF3, located upstream of the PKS genes, closely resembles the FADH
2
-dependent halogenases involved in the formation of halometabolites. The ORF3 protein could be responsible for the halogenation of NCZs, presenting a unique example of a halogenase involved in the biosynthesis of an aliphatic halometabolite.
Increased Serum Resistance in
Klebsiella pneumoniae
Strains Producing Extended-Spectrum β-Lactamases
Authors: Sahly H. , Aucken H. , Benedí V. J. , Forestier C. , Fussing V. , Hansen D. S. , Ofek I. , Podschun R. , Sirot D. , Tomás J. M. , Sandvang D. , Ullmann U.
Published: August 2004

The aim of this study was to determine whether there is an association between serum resistance, O serotypes, and the production of extended-spectrum β-lactamases (ESBLs) in
Klebsiella pneumoniae
. Ninety ESBL-producing and 178 non-ESBL-producing
K. pneumoniae
isolates gathered in five European countries were O serotyped and tested for sensitivity to the serum's bactericidal effect. The frequency of serum-resistant isolates was higher among ESBL-producing strains (30%; 27/90 isolates) than among non-ESBL-producing strains (17.9%; 32/178 isolates) (
P
= 0.037; odds ratio [OR] = 1.96; 95% confidence interval [95% CI] = 1.08 to 3.53). Although O1 was the most common O serotype in both
Klebsiella
groups, its frequency among ESBL-producing strains was significantly higher (59%; 53/90 isolates) than among non-ESBL producers (36%; 64/178 isolates) (
P
= 0.0006; OR = 2.5; 95% CI = 1.52 to 4.29). Furthermore, the prevalence of the O1 serotype was higher among serum-resistant strains of both ESBL-producing (74%; 20/27isolates) and non-ESBL producers (75%; 24/32 isolates) than among serum-sensitive ESBL producers (52.4%; 33/63 isolates) and non-ESBL producers (27.4%; 40/146 isolates). Serum resistance among ESBL-producing strains (36%; 17/47 isolates) versus non-ESBL-producing strains (16%; 27/166 isolates) was also significantly higher after the exclusion of clonal strains (
P
= 0.0056; OR = 2.9; 95% CI = 1.41 to 6.01). Sixteen ESBL types were detected, among which the frequency of serum resistance was significantly lower among the SHV-producing strains (9/48 isolates) than among the TEM producers (16/35 isolates) (
P
= 0.016; OR = 3.65; CI = 1.3 to 9.7). Curing ESBL-coding plasmids did not influence the serum resistance of the bacteria; all six plasmid-cured derivatives maintained serum resistance. The present findings suggest that ESBL-producing strains have a greater pathogenic potential than non-ESBL-producing strains, but the linkage between O serotypes, serum resistance, and ESBL production remains unclear at this stage.
Efavirenz Therapy in Rhesus Macaques Infected with a Chimera of Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1
Authors: Hofman Michael J. , Higgins Joanne , Matthews Timothy B. , Pedersen Niels C. , Tan Chalet , Schinazi Raymond F. , North Thomas W.
Published: August 2004

The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5.9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.
Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine
Authors: Tenney D. J. , Levine S. M. , Rose R. E. , Walsh A. W. , Weinheimer S. P. , Discotto L. , Plym M. , Pokornowski K. , Yu C. F. , Angus P. , Ayres A. , Bartholomeusz A. , Sievert W. , Thompson G. , Warner N. , Locarnini S. , Colonno R. J.
Published: August 2004

Entecavir (ETV) exhibits potent antiviral activity in patients chronically infected with wild-type or lamivudine (3TC)-resistant (3TC
r
) hepatitis B virus (HBV). Among the patients treated in phase II ETV clinical trials, two patients for whom previous therapies had failed exhibited virologic breakthrough while on ETV. Isolates from these patients (arbitrarily designated patients A and B) were analyzed genotypically for emergent substitutions in HBV reverse transcriptase (RT) and phenotypically for reduced susceptibility in cultures and in HBV polymerase assays. After 54 weeks of 3TC therapy, patient A (AI463901-A) received 0.5 mg of ETV for 52 weeks followed by a combination of ETV and 100 mg of 3TC for 89 weeks. Viral rebound occurred at 133 weeks after ETV was started. The 3TC
r
RT substitutions rtV173L, rtL180M, and rtM204V were present at study entry, and the additional substitutions rtI169T and rtM250V emerged during ETV-3TC combination treatment. Reduced ETV susceptibility in vitro required the rtM250V substitution in addition to the 3TC
r
substitutions. For liver transplant patient B (AI463015-B), previous famciclovir, ganciclovir, foscarnet, and 3TC therapies had failed, and RT changes rtS78S/T, rtV173L, rtL180M, rtT184S, and rtM204V were present at study entry. Viral rebound occurred after 76 weeks of therapy with ETV at 1.0 mg, with the emergence of rtT184G, rtI169T, and rtS202I substitutions within the preexisting 3TC
r
background. Reduced susceptibility in vitro was highest when both the rtT184G and the rtS202I changes were combined with the 3TC
r
substitutions. In summary, infrequent ETV resistance can emerge during prolonged therapy, with selection of additional RT substitutions within a 3TC
r
HBV background, leading to reduced ETV susceptibility and treatment failure.
Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir
Authors: Kern Earl R. , Collins Deborah J. , Wan W. Brad , Beadle James R. , Hostetler Karl Y. , Quenelle Debra C.
Published: August 2004

To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log
10
-fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.
Mutation in Enterovirus 71 Capsid Protein VP1 Confers Resistance to the Inhibitory Effects of Pyridyl Imidazolidinone
Authors: Shih Shin-Ru , Tsai Mun-Chung , Tseng Sung-Nien , Won Kuo-Fang , Shia Kak-Shan , Li Wen-Tai , Chern Jyh-Haur , Chen Guang-Wu , Lee Chung-Chi , Lee Yen-Chun , Peng Kuan-Chang , Chao Yu-Sheng
Published: August 2004

Enterovirus 71 is one of the most important pathogens in the family of
Picornaviridae
that can cause severe complications in the postpoliovirus era, such as encephalitis, pulmonary edema, and even death. Pyridyl imidazolidinone is a novel class of potent and selective human enterovirus 71 inhibitor. Pyridyl imidazolidinone was identified by using computer-assisted drug design. This virologic investigation demonstrates that BPR0Z-194, one of the pyridyl imidazolidinones, targets enterovirus 71 capsid protein VP1. Time course experiments revealed that BPR0Z-194 effectively inhibited virus replication in the early stages, implying that the compound can inhibit viral adsorption and/or viral RNA uncoating. BPR0Z-194 was used to select and characterize the drug-resistant viruses. Sequence analysis of the VP1 region showed that the resistant variants differed consistently by seven amino acids in VP1 region from their parental drug-sensitive strains. Site-directed mutagenesis of enterovirus 71 infectious cDNA revealed that a single amino acid alteration at the position 192 of VP1 can confer resistance to the inhibitory effects of BPR0Z-194.
Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects
Authors: Krieter Philip , Flannery Brian , Musick Timothy , Gohdes Mark , Martinho Monika , Courtney Rachel
Published: August 2004

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 μCi) oral dose of [
14
C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.
SRI-286, a Thiosemicarbazole, in Combination with Mefloquine and Moxifloxacin for Treatment of Murine
Mycobacterium avium
Complex Disease
Authors: Bermudez Luiz E. , Kolonoski Peter , Seitz Lianne E. , Petrofsky Mary , Reynolds Robert , Wu Martin , Young Lowell S.
Published: August 2004

Treatment of
Mycobacterium avium
disease remains challenging when macrolide resistance develops. We infected C57 beige mice and treated them with mefloquine, SRI-286, and moxifloxacin. SRI-286 (80 mg/kg) was bactericidal in the liver. Mefloquine plus moxifloxacin or mefloquine plus SRI-286 were better than mefloquine alone.
Emergence of Macrolide-Resistant
Streptococcus pyogenes
Strains in French Children
Authors: Bingen Edouard , Bidet Philippe , Mihaila-Amrouche Liliana , Doit Catherine , Forcet Samuel , Brahimi Naïma , Bouvet Anne , Cohen Robert
Published: August 2004

We studied the antimicrobial susceptibility of 322
Streptococcus pyogenes
throat isolates from French children and their serotype and genomic diversity. A total of 22.4% were erythromycin resistant, and 69.4, 4.2, and 26.4% of these isolates harbored
ermB
,
ermA
, and
mefA
, respectively. Increasing resistance in France is mainly associated with a few
emm
type 28 clones.
An Internationally Spread Clone of
Streptococcus pneumoniae
Evolves from Low-Level to Higher-Level Penicillin Resistance by Uptake of Penicillin-Binding Protein Gene Fragments from Nonencapsulated Pneumococci
Authors: Hauser Christoph , Aebi Suzanne , Mühlemann Kathrin
Published: August 2004

Low-level penicillin resistance in an international
Streptococcus pneumoniae
serotype 19F clone emerging in Switzerland was characterized by mutations in the penicillin-binding protein PBP2x. Some isolates of this clone had evolved to higher resistance levels (penicillin MICs of 0.094 and 1 μg/ml), probably by acquisition of
pbp2x
fragments from local nonencapsulated pneumococci.
T2182C Mutation in 23S rRNA Is Associated with Clarithromycin Resistance in
Helicobacter pylori
Isolates Obtained in Bangladesh
Authors: Khan Rasel , Nahar Shamsun , Sultana Jinath , Ahmad Mian Mashhud , Rahman Motiur
Published: August 2004

Twelve clarithromycin-resistant (MIC, ≥1 μg/ml)
Helicobacter pylori
isolates were analyzed for point mutations in the 23S rRNA gene. Sequence analysis of all of the resistant isolates revealed a T-to-C transition mutation at position 2182. Transformation experiments confirmed that a single T-to-C transition mutation at position 2182 is associated with clarithromycin resistance.
Isolation of an Integron-Borne
bla
VIM-4
Type Metallo-β-Lactamase Gene from a Carbapenem-Resistant
Pseudomonas aeruginosa
Clinical Isolate in Hungary
Authors: Libisch Balázs , Gacs Mária , Csiszár Károly , Muzslay Mónika , Rókusz László , Füzi Miklós
Published: August 2004

The first integron-borne metallo-β-lactamase gene was isolated in Hungary. The
bla
VIM-4
gene is located on a class 1 integron that also carries a novel
bla
OXA
-like gene. The integron is harbored by a serotype O12
Pseudomonas aeruginosa
strain and shows high structural similarity to integrons isolated in Greece and Poland.
Biochemical Characterization of Laboratory Mutants of Extended-Spectrum β-Lactamase TEM-60
Authors: Caporale Bibiana , Franceschini Nicola , Perilli Mariagrazia , Segatore Bernardetta , Rossolini Gian Maria , Amicosante Gianfranco
Published: August 2004

Three mutants of the extended-spectrum β-lactamase TEM-60, the P51L, K104E, and S164R mutants, were constructed by site-directed mutagenesis. The kinetic parameters of the mutated enzymes and interactions of inhibitors were significantly different from those of TEM-60, revealing that the L51P mutation plays an important role in enzyme activity and stability in the TEM-60 background.
Clinical-Use-Associated Decrease in Susceptibility of Vancomycin-Resistant
Enterococcus faecium
to Linezolid: a Comparison with Quinupristin-Dalfopristin
Authors: Raad Issam I. , Hanna Hend A. , Hachem Ray Y. , Dvorak Tanya , Arbuckle Rebecca B. , Chaiban Gassan , Rice Louis B.
Published: August 2004

The susceptibility of 135 vancomycin-resistant
Enterococcus faecium
bacteremic isolates to linezolid and quinupristin-dalfopristin was determined. All were susceptible to linezolid, while 88% were susceptible to quinupristin-dalfopristin prior to the clinical use of the drugs at our hospital. More than 6 months after their clinical use, a decrease in susceptibility was noted for only linezolid at 83%. This was related in part to a single G2576U gene mutation in domain V of the 23S rRNA gene.
A Fusidic Acid-Resistant Epidemic Strain of
Staphylococcus aureus
Carries the
fusB
Determinant, whereas
fusA
Mutations Are Prevalent in Other Resistant Isolates
Authors: O'Neill Alexander J. , Larsen Anders R. , Henriksen Anne S. , Chopra Ian
Published: August 2004

Fusidic acid-resistant epidemic
Staphylococcus aureus
strains causing impetigo bullosa have been reported in Scandinavia. We show that these strains form part of a European epidemic clonotype that carries the
fusB
determinant. In contrast, resistance to fusidic acid in a collection of nonepidemic strains resulted primarily from mutations in
fusA
.
Drug Susceptibility and Genetic Evaluation of
Plasmodium falciparum
Isolates Obtained in Four Distinct Geographical Regions of Kenya
Authors: Mbaisi Abigael , Liyala Pamela , Eyase Fredrick , Achilla Rachel , Akala Hosea , Wangui Julia , Mwangi Josphat , Osuna Finnley , Alam Uzma , Smoak Bonnie L. , Davis Jon M. , Kyle Dennis E. , Coldren Rodney L. , Mason Carl , Waters Norman C.
Published: August 2004

The drug resistance profiles of
Plasmodium falciparum
isolated from four regions in Kenya were analyzed for drug resistance profiles. We observed variability in resistance to a broad range of antimalarial drugs across Kenya as determined from in vitro drug susceptibility screening and genotyping analysis.
Distribution of Amphotericin B-Arabinogalactan Conjugate in Mouse Tissue and Its Therapeutic Efficacy against Murine Aspergillosis
Authors: Falk Rama , Grunwald Jacob , Hoffman Amnon , Domb Abraham J. , Polacheck Itzhack
Published: August 2004

The pharmacokinetic characteristics and tissue distribution of a novel water-soluble, nontoxic amphotericin B-arabinogalactan (AMB-AG) conjugate exhibited distinct differences from those of micellar and liposomal amphotericin B formulations. These differences included extended persistence of drug in the body and its accumulation in the lungs; thus, the AMB-AG conjugate was highly effective in treating systemic murine aspergillosis.
Convenient Biological Assay for Polyethylene Glycol-Interferons in Patients with Hepatitis C
Authors: Boulestin Anne , Kamar Nassim , Legrand-Abravanel Florence , Sandres-Saune Karine , Alric Laurent , Vinel Jean-Pierre , Rostaing Lionel , Izopet Jacques
Published: August 2004

The vesicular stomatitis virus cytopathic effect reduction assay is suitable to quantify polyethylene glycol-alpha interferon 2a (PEG-IFN-α2a) and PEG-IFN-α2b. Human serum and ribavirin did not interfere with the assay. This bioassay was successfully used for assaying PEG-IFN-α2a and PEG-IFN-α2b in serum samples from patients undergoing combination therapy.
Local Genetic Patterns within a Vancomycin-Resistant
Enterococcus faecalis
Clone Isolated in Three Hospitals in Portugal
Authors: Novais Carla , Coque Teresa M. , Sousa João Carlos , Baquero Fernando , Peixe Luisa
Published: August 2004

Eight pulsed-field gel electrophoresis subtypes and six Tn
1546
variants were identified among
Enterococcus faecalis
isolates of a single clone recovered in three geographically separate Portuguese hospitals. Some clonal subtypes were found in particular hospitals, and Tn
1546
variants were either widespread or confined to some of them. We also report on the first Tn
1546
transposon containing an IS
Ef1
insertion.
Colonization with Extraintestinal Pathogenic
Escherichia coli
among Nursing Home Residents and Its Relationship to Fluoroquinolone Resistance
Authors: Maslow Joel N. , Lautenbach Ebbing , Glaze Thomas , Bilker Warren , Johnson James R.
Published: August 2004

In a cross-sectional fecal prevalence survey involving 49 residents of a Veterans Affairs nursing home, 59% of subjects were colonized with extraintestinal pathogenic
Escherichia coli
(ExPEC), 22% were colonized with adhesin-positive
E. coli
, and 51% were colonized with fluoroquinolone-resistant
E. coli
. Among 80 unique isolates, adhesins correlated negatively and aerobactin correlated positively with fluoroquinolone resistance.
National Surveillance of Methicillin-Resistant
Staphylococcus aureus
in Belgian Hospitals Indicates Rapid Diversification of Epidemic Clones
Authors: Denis Olivier , Deplano Ariane , Nonhoff Claire , De Ryck Raf , de Mendonça Ricardo , Rottiers Sylvianne , Vanhoof Raymond , Struelens Marc J.
Published: August 2004

Methicillin-resistant
Staphylococcus aureus
(MRSA) strains (
n
= 455) collected in 2001 from 100 Belgian hospitals were characterized by molecular typing and by resistance gene distribution to macrolides-lincosamides-streptogramins and to aminoglycoside antibiotics. Rapid diversification of MRSA clones, compared with results of previous surveys, was evidenced by the broad geographic distribution of seven major clones belonging to the pandemic MRSA clonal complexes 5, 8, 22, 30, and 45 by multilocus sequence typing.
Designing Fluoroquinolone Breakpoints for
Streptococcus pneumoniae
by Using Genetics instead of Pharmacokinetics-Pharmacodynamics
Authors: Smith H. J. , Noreddin A. M. , Siemens C. G. , Schurek K. N. , Greisman J. , Hoban C. J. , Hoban D. J. , Zhanel G. G.
Published: August 2004

We determined fluoroquinolone microbiological resistance breakpoints for
Streptococcus pneumoniae
by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.
Invasive
Streptococcus pneumoniae
in France: Antimicrobial Resistance, Serotype, and Molecular Epidemiology Findings from a Monthly National Study in 2000 to 2002
Authors: Decousser Jean-Winoc , Pina Patrick , Viguier Florent , Picot Franc , Courvalin Patrice , Allouch Pierre
Published: August 2004

A study of 257 French invasive pneumococci isolated between 2000 and 2002 showed high rates of nonsusceptibility to penicillin and macrolides (50%), contrasting with a low frequency of resistance to amoxicillin or levofloxacin (<1%) and tolerance to vancomycin (0%). The genetic homogeneity of some serogroups, including serogroup 1, enhanced the risk of epidemiological changes.
SOFT ERRORS IN COMMERCIAL INTEGRATED CIRCUITS
Authors: BAUMANN R. C.
Published: August 2004

The once-ephemeral soft error has recently caused considerable concern for manufacturers of advanced silicon technology as this phenomenon now has the potential for inducing the highest failure rate of all other reliability mechanisms combined. We briefly review the three radiation mechanisms responsible for causing soft errors in commercial electronics and the basic physical mechanism by which ionizing radiation can produce a soft error. We then focus on the soft error sensitivity trends in commercial DRAM, SRAM, and peripheral logic devices as a function of technology scaling and discuss some of the solutions used for mitigating the impact of soft errors in high reliability systems.
SINGLE-EVENT EFFECTS IN III-V SEMICONDUCTOR ELECTRONICS
Authors: McMORROW DALE , MELINGER JOSEPH S. , KNUDSON ALVIN R.
Published: August 2004

Single-event effects are a serious concern for high-speed III-V semiconductor devices operating in radiation-intense environments. GaAs integrated circuits (ICs) based on field effect transistor technology exhibit single-event upset sensitivity to protons and very low linear energy transfer (LET) particles. The current understanding of single-event effects in III-V circuits and devices, and approaches for mitigating their impact, are discussed.
INVESTIGATION OF SINGLE-EVENT TRANSIENTS IN FAST INTEGRATED CIRCUITS WITH A PULSED LASER
Authors: Fouillat P. , Pouget V. , Lewis D. , Buchner S. , McMorrow D.
Published: August 2004

This paper describes the use of a pulsed laser for studying radiation-induced single-event transients in integrated circuits. The basic failure mechanisms and the fundamentals of the laser testing method are presented. Sample results are presented to illustrate the benefits of using a pulsed laser for studying single-event transients.
RADIATION-TOLERANT DESIGN FOR HIGH PERFORMANCE MIXED-SIGNAL CIRCUITS
Authors: HOLMAN W. T.
Published: August 2004

Modern semiconductor processes can provide significant intrinsic hardness against radiation effects in digital and analog circuits. Current design techniques using commercial processes for radiation-tolerant integrated circuits are summarized, with an emphasis on their application in high performance mixed-signal circuits and systems. Examples of "radiation hardened by design" (RHBD) methodologies are illustrated for reducing the vulnerability of circuits and components to total dose, single-event, and dose-rate effects.
A TOTAL-DOSE HARDENING-BY-DESIGN APPROACH FOR HIGH-SPEED MIXED-SIGNAL CMOS INTEGRATED CIRCUITS
Authors: NOWLIN NATHAN , BAILEY JOHN , TURFLER BOB , ALEXANDER DAVE
Published: August 2004

This paper describes design choices and tradeoffs made when designing total-dose hardness into an advanced CMOS integrated circuit. Closed geometry transistors are described and compared, emphasizing their radiation tolerant performance. Speed and area tradeoffs incurred in circuit design when using such closed geometry transistors are illustrated in the design of an advanced IEEE 1394 cable physical layer mixed-signal interface chip.
RADIATION ISSUES IN THE NEW GENERATION OF HIGH ENERGY PHYSICS EXPERIMENTS
Authors: FACCIO F.
Published: August 2004

With the construction of the Large Hadron Collider at the European Center for Nuclear Research (CERN), the radiation levels at large High Energy Physics (HEP) experiments are significantly increased with respect to past experience. The approach the HEP community is using to ensure radiation tolerance of the electronics installed in these new generation experiments is described. Particular attention is devoted to developments that led to original work: the estimate of the SEU rate in the complex LHC radiation environment and the use of hardness by design techniques to achieve radiation hardness of ASICs in a commercial CMOS technology.
SPACE RADIATION EFFECTS IN OPTOCOUPLERS
Authors: REED ROBERT A. , MARSHALL PAUL W. , LABEL KENNETH A.
Published: August 2004

Assessing the risk of using optocouplers in satellite applications offers challenges that incorporate those of commercial off-the-shelf devices compounded by hybrid module construction techniques. In this paper, we discuss these challenges with regard to radiation-induced effects, e.g., single event transients in the photodiodes and displacement damage effects in light emitting diodes. Radiation-induced effects can depend on several important variables including circuit application, radiation environment, annealing, temperature, and others. Despite the ominous list of test variables above, it is possible to make a conservative estimate of optocoupler performance in the space radiation environment. However, these predictions could result in an overestimation of on-orbit performance by an order of magnitude or more.
RADIATION EFFECTS IN CHARGE-COUPLED DEVICE (CCD) IMAGERS AND CMOS ACTIVE PIXEL SENSORS
Authors: HOPKINSON G. R. , MOHAMMADZADEH A.
Published: August 2004

This review concerns radiation effects in silicon Charge-Coupled Devices (CCDs) and CMOS active pixel sensors (APSs), both of which are used as imagers in the visible region. Permanent effects, due to total ionizing dose and displacement damage, are discussed in detail, with a particular emphasis on the space environment. In addition, transient effects are briefly summarized. Implications for ground testing, effects mitigation and device hardening are also considered. The review is illustrated with results from recent ground testing.
THE EFFECTS OF SPACE RADIATION EXPOSURE ON POWER MOSFETS: A REVIEW
Authors: SHENAI K. , GALLOWAY K.F. , SCHRIMPF R.D.
Published: August 2004

Power MOSFETs are a commonly used device for many switching and power control applications. Their upper frequency limit spans a fairly broad range, from 1 MHz to 10 MHz. These devices are frequently used in spaceborne electronic systems where they encounter radiation exposure during operation. This paper reviews the current technology, its high frequency capability, the future trends for power MOSFET technology, and the degradation that the power VDMOS technology experiences in the space radiation environment.
INTRODUCTION TO SOI MOSFETs: CONTEXT, RADIATION EFFECTS, AND FUTURE TRENDS
Authors: CRISTOLOVEANU SORIN , FERLET-CAVROIS VÉRONIQUE
Published: August 2004

The context of SOI technology is briefly presented in terms of wafer fabrication, configuration/performance of SOI devices, and operation mechanisms in partially and fully depleted MOSFETs. Typical radiation effects, induced by single particles and cumulated dose, are evoked: BOX degradation, parasitic bipolar action, coupling effects, transistor latch, and back-channel conduction. The future of SOI is tentatively explored, by discussing the further scalability of SOI-MOSFETs as well as the innovating architectures proposed for the ultimate generations of SOI transistors.
TOTAL DOSE EFFECTS IN LINEAR BIPOLAR INTEGRATED CIRCUITS
Authors: BARNABY H. J.
Published: August 2004

Electronics systems that operate in space or strategic environments can be severely damaged by exposure to ionizing radiation. Space-based systems that utilize linear bipolar integrated circuits are particularly susceptible to radiation-induced damage because of the enhanced sensitivity of these circuits to the low rate of radiation exposure. The phenomenon of enhanced low-dose-rate sensitivity (ELDRS) demonstrates the need for a comprehensive understanding of the mechanisms of total dose effects in linear bipolar circuits. The majority of detailed bipolar total dose studies to date have focused on radiation effects mechanisms at either the process or transistor level. The goal of this text is to provide an overview of total dose mechanisms from the circuit perspective; in particular, the effects of transistor gain degradation on specific linear bipolar circuit parameters and the effects of circuit parameter degradation on select linear bipolar circuit applications.
HARDNESS ASSURANCE FOR COMMERCIAL MICROELECTRONICS
Authors: PEASE RONALD L.
Published: August 2004

An approach to hardness assurance for commercial microelectronics is presented based on hardness assurance guidelines developed by the US Department of Defense in the late 1970s and early 1980s. Modifications are made to accommodate commercial variability in radiation response and frequent changes in design and process.
IONIZING RADIATION EFFECTS ON ULTRA-THIN OXIDE MOS STRUCTURES
Authors: CESTER A. , PACCAGNELLA A.
Published: August 2004

We have briefly reviewed the most important degradation mechanisms affecting ultra-thin gate oxides after exposure to ionizing irradiation. The increase of the gate leakage current seems the most crucial issue for device lifetime, especially for non-volatile memory and dynamic logic. The build-up of positive charge in the oxide and the subsequent threshold voltage shift, which was the major concern for thicker oxide, are no longer appreciable in today's devices due to the reduced oxide thickness permitting a fast recombination of trapped holes with electrons from interfaces. Among the leakage currents affecting thin oxides we have considered here the Radiation Induced Leakage Current (RILC) and the Radiation Soft Breakdown (RSB). RILC is observed after irradiation with a low Linear Energy Transfer (LET) radiation source and comes from a trap-assisted tunneling of electrons mediated by the neutral traps produced by irradiation. RILC depends on the applied bias during irradiation and the maximum is measured when devices are biased in flat band. Contrarily to RILC, RSB is observed after irradiation with high LET ions and derives from the formation of several conductive paths across the oxide corresponding to the ion hits. RSB conduction is explained by the theory of the Quantum Point Contact as also proposed for the electrically induced Soft breakdown. Finally, we present some preliminary results, which indicate that although the direct effects of irradiation (in terms of gate leakage current increase) are small for oxide thinner than 3nm, it is possible that these devices may experience an accelerated wear-out and/or breakdown after subsequent electrical stress relative to a fresh (not irradiated) device.
HYDROGEN AT THE Si/SiO2 INTERFACE: FROM ATOMIC-SCALE CALCULATIONS TO ENGINEERING MODELS
Authors: RASHKEEV S. N. , FLEETWOOD D. M. , SCHRIMPF R. D. , PANTELIDES S. T.
Published: August 2004

Two contrasting behaviors have been observed for H in Si / SiO 2 structures: a) Radiation experiments established that protons released in SiO 2 migrate to the Si / SiO 2 interface where they induce new defects; b) For oxides exposed first to high-temperature annealing and then to molecular hydrogen, mobile positive charge believed to be protons can be cycled to and from the interface by reversing the oxide electric field. First-principles density functional calculations identify the atomic-scale mechanisms for the two types of behavior and conditions that are necessary for each. Using the results of the atomic-scale calculations we develop a model for enhanced interface-trap formation at low dose rates due to space charge effects in the base oxides of bipolar devices. We find that the hole trapping in the oxide cannot be responsible for all the Enhanced Low-Dose-Rate Sensitivity (ELDRS) effects in SiO 2, and the contribution of protons is also essential. The dynamics of interface-trap formation are defined by the relation between the proton mobility (transport time of the protons across the oxide) and the time required for positive-charge buildup near the interface due to trapped holes. The analytically estimated and numerically calculated interface-trap densities are found to be in very good agreement with available experimental data.
SWITCHING OXIDE TRAPS
Authors: OLDHAM TIMOTHY R.
Published: August 2004

Positive oxide trapped charge is one of the main factors determining the radiation response of a CMOS device. The most widely accepted model for oxide-trapped charge is the dipole model, originally proposed by Lelis et al. The annealing of radiation-induced positive trapped charge proceeds (usually) via the tunneling of electrons, which form metastable dipoles, compensating the trapped positive charge without removing it. Under appropriate bias, these compensating electrons can tunnel back to the Si substrate, restoring the trapped positive charge. The experimental work leading to the development of this model is summarized. By now there is a large body of experimental and theoretical work by others, confirming and extending the original model. In particular, the relevance of the model to some electron trapping studies has been shown, and its application to the larger topic of oxide reliability is discussed.
ONLINE AND REALTIME DOSIMETRY USING OPTICALLY STIMULATED LUMINESCENCE
Authors: DUSSEAU L. , GASIOT J.
Published: August 2004

A new generation of Optically stimulated materials has been synthesized at the University Montpellier II. The very high sensitivity of these phosphors, the short time constant of the luminescence and the perfectly separated spectra enable many applications in real time and online dosimetry. Dosimetry can be considered as real-time when the dose change between two measurements is considered as low enough. For satellite applications, we have developed an integrated sensor to measure the dose received orbit by orbit. In radiotherapy, OSL has been used to control the dose deposited during intra-operative in-vivo irradiation. At CERN, we have proposed an online system to monitor the dose simultaneously in about one hundred locations inside the Compact Muon Solenoid (CMS) experiment.
ELECTROMAGNETIC DUALITY ON THE LIGHT-FRONT IN THE PRESENCE OF EXTERNAL SOURCES
Authors: MUKHERJEE ASMITA , BHATTACHARYA SOMDATTA
Published: August 2004

We investigate the issue of electromagnetic duality on the light-front. We work with Zwanziger's theory of electric and magnetic sources which is appropriate for treating duality. When quantized on the light-front in the light-front gauge, this theory yields two independent phase space degrees of freedom, namely the two transverse field components, the right number to describe the gauge field sector of normal light-front QED and also the appropriate commutator between them. The electromagnetic duality transformation formulated in terms of them is similar in form to the Susskind transformation proposed for the free theory, provided one identifies them as the dynamical field components of the photon on the light-front in the presence of magnetic sources. The Hamiltonian density written in terms of these components is invariant under the duality transformation.
FLUX TUBE SOLUTIONS IN SQUARE ROOT GAUGE THEORY
Authors: AMER N. , GUENDELMAN E. I.
Published: August 2004

Flux tube solutions are found in the square root gauge theory. Purely magnetic solutions exist which do not contain radiation. It is found that no electric monopole solution exists, which is a sign of electric charge confinement, but magnetic monopole solutions exist and therefore there is no confinement of magnetic charge. There are also solutions which have both electric and magnetic components and represent flux tubes where in addition some radiation process, caused for example by some annihilation in the center of the tube takes place. Finally, there are solutions with both electric and magnetic field which do not represent radiation but rather electric flux tubes, which are good candidates for describing confinement of oppositely charged sources. Demanding angular momentum quantization leads to the quantization of the length of these tubes.
GAUGE DEPENDENCE IN THE AdS/CFT CORRESPONDENCE
Authors: GIROTTI H. O. , RIVELLES VICTOR O.
Published: August 2004

We consider the AdS space formulation of the classical dynamics deriving from the Stückelberg Lagrangian. The on-shell action is shown to be free of infrared singularities as the vector boson mass tends to zero. In this limit the model becomes Maxwell theory formulated in an arbitrary covariant gauge. Then we use the AdS/CFT correspondence to compute the two-point correlation functions on the boundary. It is shown that the gauge dependence concentrates on the contact terms while the nontrivial part of the conformal theory correlators turns out to be that already found by working in a completely fixed gauge.
COSMIC STRING LOOPS COLLAPSING TO BLACK HOLES
Authors: HANSEN R. N. , CHRISTENSEN M. , LARSEN A. L.
Published: August 2004

We examine the question of collapse of Turok's two-parameter family of cosmic strings. We first perform a classification of the strings according to the specific time(s) at which the minimal string size is reached during one period. We then obtain an exact analytical expression for the probability of collapse to black holes for the Turok strings. Our result has the same general behavior as previously obtained in the literature but we find, in addition, a numerical prefactor that changes the result by three orders of magnitude. Finally we show that our careful computation of the prefactor helps us to understand the discrepancy between previously obtained results and, in particular, that for "large" values of Gμ, there may not even be a discrepancy. We also give a simple physical argument that can immediately rule out some of the previously obtained results.
ON THE RENORMALIZABILITY OF THEORIES WITH GAUGE ANOMALIES
Authors: CASANA RODOLFO , DIAS SEBASTIÃO A.
Published: August 2004

We consider the detailed renormalization of two (1+1)-dimensional gauge theories which are quantized without preserving gauge invariance: the chiral and the "anomalous" Schwinger models. By regularizing the nonperturbative divergences that appear in fermionic Green functions of both models, we show that the "tree level" photon propagator is ill defined, thus forcing one to use the complete photon propagator in the loop expansion of these functions. We perform the renormalization of these divergences in both models to one-loop level, defining it in a consistent and semiperturbative sense that we propose in this paper.
ACTION WITH MANIFEST DUALITY FOR MAXIMALLY SUPERSYMMETRIC SIX-DIMENSIONAL SUPERGRAVITY
Authors: DE POL GIANCARLO , TONIN MARIO , SINGH HARVENDRA
Published: August 2004

We perform explicitly the toroidal compactification of eleven-dimensional supergravity to six dimensions and present its action in a manifestly [Formula: see text] invariant form using the recently proposed covariant formulation of theories involving chiral fields.
FIRST ORDER QUANTUM CORRECTIONS TO THE CLASSICAL REFLECTION FACTOR OF THE SINH–GORDON MODEL
Authors: CHENAGHLOU A. , CORRIGAN E.
Published: August 2004

The sinh–Gordon model is restricted to a half-line by boundary conditions maintaining integrability. A perturbative calculation of the reflection factor is given to one loop order in the bulk coupling and to first order in the difference of the two parameters introduced at the boundary, providing a further verification of Ghoshal's formula. The calculation is consistent with a conjecture for the general dependence of the reflection factor on the boundary parameters and the bulk coupling.
THE REST-FRAME INSTANT FORM OF RELATIVISTIC PERFECT FLUIDS WITH EQUATION OF STATE ρ=ρ(n, s) AND OF NONDISSIPATIVE ELASTIC MATERIALS
Authors: LUSANNA LUCA , NOWAK-SZCZEPANIAK DOBROMILA
Published: August 2004

For perfect fluids with equation of state ρ=ρ(n, s), Brown1 gave an action principle depending only on their Lagrange coordinates αi(x) without Clebsch potentials. After a reformulation on arbitrary spacelike hypersurfaces in Minkowski space–time, the Wigner-covariant rest-frame instant form of these perfect fluids is given. Their Hamiltonian invariant mass can be given in closed form for the dust and the photon gas. The action for the coupling to tetrad gravity is given. Dixon's multipoles for the perfect fluids are studied on the rest-frame Wigner hyperplane. It is also shown that the same formalism can be applied to nondissipative relativistic elastic materials described in terms of Lagrangian coordinates.
LOOP VARIABLES AND GAUGE-INVARIANT INTERACTIONS — I
Authors: SATHIAPALAN B.
Published: August 2004

We describe a method of writing down interacting equations for all the modes of the bosonic open string. It is a generalization of the loop variable approach that was used earlier for the free, and lowest order interacting cases. The generalization involves, as before, the introduction of a parameter to label the different strings involved in an interaction. The interacting string has thus becomes a "band" of finite width. The interaction equations expressed in terms of loop variables, has a simple invariance that is exact even off shell. A consistent definition of space–time fields requires the fields to be functions of all the infinite number of gauge coordinates (in addition to space–time coordinates). The theory is formulated in one higher dimension, where the modes appear massless. The dimensional reduction that is needed to make contact with string theory (which has been discussed earlier for the free case) is not discussed here.
EXACT SOLUTIONS OF THE DIRAC EQUATION FOR MODIFIED COULOMBIC POTENTIALS
Authors: DE CASTRO ANTONIO SOARES , FRANKLIN JERROLD
Published: August 2004

Exact solutions are found for the Dirac equation for a combination of Lorentz scalar and vector Coulombic potentials with additional non-Coulombic parts. An appropriate linear combination of Lorentz scalar and vector non-Coulombic potentials, with the scalar part dominating, can be chosen to give exact analytic Dirac wave functions. The method works for the ground state or for the lowest orbital state with l=j-½, for any j.
COLLECTIVE AND RELATIVE VARIABLES FOR MASSLESS FIELDS
Authors: ASSENZA L. , LONGHI G.
Published: August 2004

In this paper, a set of canonical collective and relative variables for a classical relativistic massless field are defined and discussed. The discussion is based on a harmonic analysis on the light-cone in momentum space.

It is shown how to avoid a set of consistency constraints which are necessary in the massive case.

As a result a canonical separation of the angular momentum in collective and relative parts and a canonical realization of an extended BMS algebra are obtained.