bluuebunny/crossref_metadata_2025 huggingface dataset:
LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant
Staphylococcus aureus
Authors: Vouillamoz Jacques , Entenza José M. , Hohl Peter , Moreillon Philippe
Published: October 2004

LB11058 is a new synthetic cephalosporin with good affinity for staphylococcal penicillin-binding protein 2a (PBP2a). LB11058 was tested in vitro and in rats with experimental aortic endocarditis against three methicillin-resistant
Staphylococcus aureus
(MRSA) strains, one penicillinase-negative strain (strain COL), and two penicillinase-producing strains (COL-Bla+ and P8-Hom). The MICs of LB11058 for the organisms were 1 mg/liter. The MICs of vancomycin and ceftriaxone were 1 and ≥64 mg/liter, respectively. In population analysis profiles, none of the MRSA strains grew at ≥2 mg of LB11058/liter. Rats with endocarditis were treated for 5 days. LB11058 was highly bound to serum proteins in rats (≥98%). However, binding was saturable above a threshold of 250 mg/liter. Therefore, continuous concentrations of 250 mg/liter in serum were infused to ensure a free fraction (≥5 mg/liter) above the drug's MIC for the entire infusion period. Control treatments included simulation of human serum kinetics produced by intravenous vancomycin (1 g twice daily, free drug concentration above MIC, ≥90% of infusion period) or ceftriaxone (2 g/24 h, free drug concentrations above the MIC, 0% of infusion period). LB11058 successfully treated 10 of 10 (100%) and 13 of 14 (93%) of rats infected with COL-Bla+ and P8-Hom, respectively. This was comparable to vancomycin (sterilization of 8 of 12 [66%] and 6 of 8 [75%] rats, respectively). Ceftriaxone was inactive. Low concentrations of LB11058 (5 and 10 mg/liter, continuously infused) in serum were ineffective, as predicted by the pharmacodynamic parameters. At appropriate doses, LB11058 was highly effective both in vitro and in vivo. This finding supports the development of this beta-lactam with high PBP2a affinity for the treatment of MRSA infections.
Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults
Authors: DiCenzo Robert , Peterson Derick , Cruttenden Kim , Morse Gene , Riggs Garret , Gelbard Harris , Schifitto Giovanni
Published: October 2004

Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n= 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n= 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in meanC0and 8-h VPA concentrations versus the control (n= 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n= 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n= 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.
Maternal-Fetal Transfer and Amniotic Fluid Accumulation of Nucleoside Analogue Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pregnant Women
Authors: Chappuy Hélène , Tréluyer Jean-Marc , Jullien Vincent , Dimet Jérôme , Rey Elisabeth , Fouché Maria , Firtion Ghislaine , Pons Gérard , Mandelbrot Laurent
Published: October 2004

This study was performed to investigate placental transfer of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their concentrations in amniotic fluid when given to human immunodeficiency virus (HIV)-infected pregnant women. A total of 100 HIV type 1-infected mothers receiving antiretroviral therapy, including one or more NRTIs, for clinical indications at the time of delivery were enrolled. Maternal blood samples and amniotic fluid were obtained during delivery or cesarean section, and paired cord blood samples were obtained by venipuncture immediately after delivery. Drug concentrations were measured by using high-performance liquid chromatography. A significant relationship between concentrations in maternal and cord plasma samples was found for zidovudine, lamivudine, stavudine, and didanosine. The ratio between the concentrations in cord and maternal plasma samples (
R
) was high for zidovudine (
R
= 1.22), its glucuronide metabolite (3′-azido-3′-deoxythymidine-β-
d
-glucuronide) (
R
= 1.01), stavudine (
R
= 1.32), lamivudine (
R
= 0.93), and abacavir (
R
= 1.03) and was low for didanosine (
R
= 0.38). The ratio between the concentrations in amniotic fluid and cord plasma samples was high for zidovudine (
R
= 2.24), its glucuronide metabolite (
R
= 2.83), stavudine (
R
= 4.87), and lamivudine (
R
= 3.99) and was lower for didanosine (
R
= 1.14). These findings indicate that most NRTIs cross the placenta by simple diffusion and are concentrated in the amniotic fluid, probably through fetal urinary excretion. The efficacy or toxicity of NRTIs may vary according to placental transfer.
Inhibition of Adherence and Killing of
Candida albicans
with a 23-Mer Peptide (Fn/23) with Dual Antifungal Properties
Authors: Klotz Stephen A. , Gaur Nand K. , Rauceo Jason , Lake Douglas F. , Park Y. , Hahm K. S. , Lipke Peter N.
Published: October 2004

Candida albicans
adheres to host tissue and then proliferates in order to establish a commensal as well as a pathogenic state. Specific adherence to proteins is provided by several surface adhesins of
Candida
. Two well-studied proteins, Als1p and Als5p, do not require energy for adherence to occur (dead as well as living cells adhere) and have a multiplier effect of cell-cell aggregation that mediates the formation of microcolonies of
Candida
cells. The entire process is spontaneous, reversible, and stable for physiologically relevant chemical and physical forces. This adherence process is inhibited by the addition of free peptide ligands, including a 23-mer derived from fibronectin (Fn/23) that binds to the adhesins through H bond formation. Adherence was measured by determining the number of yeast cells that adhered to 90-μm-diameter polyethylene glycol (PEG) beads with a 7-mer peptide (KLRIPSV) synthesized on the surfaces of the beads. The concentration of the Fn/23 peptide that inhibited the adherence of cells to the peptide-coated beads by 50% was 4 to 5 μM, and the magnitudes of adherence were similar regardless of the presence or absence of physiologic salt concentrations. The minimum fungicidal concentration of Fn/23 was 2 to 4 μM in water, but there was no killing in physiologic salt concentrations. Peptides from the C and N termini or the center sequence of Fn/23 had no effect on inhibition of adherence and little effect on fungal viability. The fungicidal effect was similar to that seen with 23-, 19-, and 18-mer peptides derived from porcine myeloid cells, a
Helicobacter pylori
ribosomal protein, and a hybrid of cecropin and magainin, respectively. However, these fungicidal peptides did not inhibit
C. albicans
adherence to the peptide-coated PEG beads. This dual property of Fn/23, i.e., inhibition of adherence and killing of
C. albicans
, may provide important adjuvant effects in the treatment of disease caused by this fungus.
Delivery of Granulocyte-Macrophage Colony-Stimulating Factor in Bioadhesive Hydrogel Stimulates Migration of Dendritic Cells in Models of Human Papillomavirus-Associated (Pre)Neoplastic Epithelial Lesions
Authors: Hubert Pascale , Evrard Brigitte , Maillard Catherine , Franzen-Detrooz Elizabeth , Delattre Luc , Foidart Jean-Michel , Noël Agnes , Boniver Jacques , Delvenne Philippe
Published: October 2004

Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were evaluated for their bioactivity and for their potential to recruit DC in organotypic cultures of HPV-transformed keratinocytes. We found that a bioadhesive polycarbophil gel (Noveon) at pH 5.5 is able to maintain the bioactivity of GM-CSF at 4 or 37°C for at least 7 days, whereas a decreased activity of GM-CSF was observed when the molecule is included in other polymer gels. GM-CSF incorporated in the polycarbophil gel was also a potent factor in enhancing the colonization of DC into organotypic cultures of HPV-transformed keratinocytes since the infiltration of DC in the in vitro-formed (pre)neoplastic epithelium was very low under basal conditions and dramatically increased in the presence of GM-CSF gel. We next demonstrated that GM-CSF incorporated in polycarbophil gel induces the recruitment of human DC in a human (pre)neoplastic epithelium grafted into NOD/SCID mice. The efficacy of GM-CSF in this formulation was equivalent to that observed with liquid GM-CSF. These results suggest that GM-CSF incorporated in polycarbophil gel could play an important role in the recruitment of DC/LC in mucosal surfaces and be useful as a new immunotherapeutic approach for genital HPV-associated (pre)neoplastic lesions.
N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion
Authors: Jiang Shibo , Lu Hong , Liu Shuwen , Zhao Qian , He Yuxian , Debnath Asim K.
Published: October 2004

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of “drug-like” compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the α-helical conformation. They blocked a
d-
peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.
Usnic Acid, a Natural Antimicrobial Agent Able To Inhibit Bacterial Biofilm Formation on Polymer Surfaces
Authors: Francolini I. , Norris P. , Piozzi A. , Donelli G. , Stoodley P.
Published: October 2004

In modern medicine, artificial devices are used for repair or replacement of damaged parts of the body, delivery of drugs, and monitoring the status of critically ill patients. However, artificial surfaces are often susceptible to colonization by bacteria and fungi. Once microorganisms have adhered to the surface, they can form biofilms, resulting in highly resistant local or systemic infections. At this time, the evidence suggests that (+)-usnic acid, a secondary lichen metabolite, possesses antimicrobial activity against a number of planktonic gram-positive bacteria, including
Staphylococcus aureus
,
Enterococcus faecalis
, and
Enterococcus faecium
. Since lichens are surface-attached communities that produce antibiotics, including usnic acid, to protect themselves from colonization by other bacteria, we hypothesized that the mode of action of usnic acid may be utilized in the control of medical biofilms. We loaded (+)-usnic acid into modified polyurethane and quantitatively assessed the capacity of (+)-usnic acid to control biofilm formation by either
S. aureus
or
Pseudomonas aeruginosa
under laminar flow conditions by using image analysis. (+)-Usnic acid-loaded polymers did not inhibit the initial attachment of
S. aureus
cells, but killing the attached cells resulted in the inhibition of biofilm. Interestingly, although
P. aeruginosa
biofilms did form on the surface of (+)-usnic acid-loaded polymer, the morphology of the biofilm was altered, possibly indicating that (+)-usnic acid interfered with signaling pathways.
Analysis of Mupirocin Resistance and Fitness in
Staphylococcus aureus
by Molecular Genetic and Structural Modeling Techniques
Authors: Hurdle Julian Gregston , O'Neill Alexander John , Ingham Eileen , Fishwick Colin , Chopra Ian
Published: October 2004

Chromosomal resistance to mupirocin in clinical isolates of
Staphylococcus aureus
arises from V
588
F or V
631
F mutations in isoleucyl-tRNA synthetase (IRS). Whether these are the only IRS mutations that confer mupirocin resistance or simply those that survive in the clinic is unknown. Mupirocin-resistant mutants of
S. aureus
8325-4 were therefore generated to examine their
ileS
genotypes and the in vitro and in vivo fitness costs associated with them before and after compensatory evolution. Most spontaneous first-step mupirocin-resistant mutants carried V
588
F or V
631
F mutations in IRS, but a new mutation (G
593
V) was also identified. Second-step mutants carried combinations of previously identified IRS mutations (e.g., V
588
F/V
631
F and G
593
V/V
631
F), but additional combinations also occurred involving novel mutations (R
816
C, H
67
Q, and F
563
L). First-step mupirocin-resistant mutants were not associated with substantial fitness costs, a finding that is consistent with the occurrence of V
588
F or V
631
F mutations in the IRS of clinical strains. Second-step mutants were unfit, but fitness could be restored by subculture in the absence of mupirocin. In most cases, this was the result of compensatory mutations that also suppressed mupirocin resistance (e.g., A
196
V, E
190
K, and E
195
K), despite retention of the original mutations conferring resistance. Structural explanations for mupirocin resistance and loss of fitness were obtained by molecular modeling of mutated IRS enzymes, which provided data on mupirocin binding and interaction with the isoleucyl-AMP reactive intermediate.
In Vitro Combination of Amdoxovir and the Inosine Monophosphate Dehydrogenase Inhibitors Mycophenolic Acid and Ribavirin Demonstrates Potent Activity against Wild-Type and Drug-Resistant Variants of Human Immunodeficiency Virus Type 1
Authors: Borroto-Esoda Katyna , Myrick Florence , Feng Joy , Jeffrey Jerry , Furman Phillip
Published: October 2004

Amdoxovir [(−)-β-
d
-2,6-diaminopurine dioxolane (DAPD)] is a nucleoside analogue reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. DAPD is deaminated by adenosine deaminase to the guanosine analogue dioxolane guanosine (DXG), which is subsequently phosphorylated to the corresponding 5′ triphosphate (DXG-TP). DXG-TP competes with the natural substrate dGTP for binding to the enzyme-nucleic acid complex. Mycophenolic acid (MPA) and ribavirin (RBV), inhibitors of inosine monophosphate dehydrogenase (IMPDH), inhibit the de novo synthesis of guanine nucleotides, including dGTP. Reducing the intracellular levels of dGTP would be expected to augment the antiviral activity of analogues of deoxyguanosine. In this study we examined the effect of MPA and RBV on the anti-HIV activity of DAPD and DXG. When tested against wild-type virus, both MPA and RBV decreased the 50% effective concentration (EC
50
) for DXG by at least 10-fold. In contrast, both MPA and RBV increase the EC
50
value for zidovudine. MPA and RBV completely reversed the resistance to DXG observed with HIV isolates containing mutations which confer partial resistance to DAPD and DXG. Similarly, when tested against a mutant virus fully resistant to inhibition by DAPD (K65R/Q151M), MPA and RBV reduced the EC
50
for DAPD to within twofold of that for the wild type. The combination of MPA or RBV with DAPD or DXG did not result in increased cytotoxicity or reduced levels of mitochondrial DNA when tested at physiologically relevant concentrations. These studies suggest a potential role for the use of IMPDH inhibitors in combination therapy with amdoxovir in the treatment of HIV.
Platelet Microbicidal Protein 1: Structural Themes of a Multifunctional Antimicrobial Peptide
Authors: Yount Nannette Y. , Gank Kimberly D. , Xiong Yan Qiong , Bayer Arnold S. , Pender Thomas , Welch William H. , Yeaman Michael R.
Published: October 2004

Mammalian platelets release platelet microbicidal proteins (PMPs) as components of their antimicrobial armamentarium. The present studies defined the structure of PMP-1 and examined its structure-activity relationships. Amino acid sequencing and mass spectroscopy demonstrated that distinct N-terminal polymorphism variants of PMP-1 isolated from nonstimulated or thrombin-stimulated platelets arise from a single PMP-1 propeptide. Sequence data (NH2-[S]D1DPKE5SEGDL10HCVCV15KTTSL20. . .) enabled cloning of PMP-1 from bone marrow and characterization of its full-length cDNA. PMP-1 is translated as a 106-amino-acid precursor and is processed to yield 73-residue (8,053 Da) and 72-residue (7,951-Da) variants. Searches with the BLAST program and sequence alignments demonstrated the homology of PMP-1 to members of the mammalian platelet factor 4 (PF-4) family of proteins. On the basis of phylogenetic relatedness, congruent sequence motifs, and predicted three-dimensional structures, PMP-1 shares the greatest homology with human PF-4 (hPF-4). By integration of its structural and antimicrobial properties, these results establish the identity of PMP-1 as a novel rabbit analogue of the microbicidal chemokine (kinocidin) hPF-4. These findings advance the hypothesis that stimuli in the setting of infection prompt platelets to release PF-4-class or related kinocidins, which have structures consistent with their likely multiple roles that bridge molecular and cellular mechanisms of antimicrobial host defense.
Anti-
Aspergillus fumigatus
Efficacy of Pentraxin 3 Alone and in Combination with Antifungals
Authors: Gaziano Roberta , Bozza Silvia , Bellocchio Silvia , Perruccio Katia , Montagnoli Claudia , Pitzurra Lucia , Salvatori Giovanni , De Santis Rita , Carminati Paolo , Mantovani Alberto , Romani Luigina
Published: October 2004

The collectin pentraxin 3 (PTX3) is an essential component of host resistance to pulmonary aspergillosis. Here we examined the protective effects of administration of PTX3 alone or together with deoxycholate amphotericin B (Fungizone) or liposomal amphotericin B (AmBisome) against invasive aspergillosis in a murine model of allogeneic bone marrow transplantation. PTX3, alone or in combination with the polyenes, was given intranasally or parenterally either before, in concomitance with, or after the intranasal infection with
Aspergillus fumigatus
conidia. Mice were monitored for resistance to infection and parameters of innate and adaptive T-helper immunity. The results showed the following: (i) complete resistance to infection and reinfection was observed in mice treated with PTX3 alone; (ii) the protective effect of PTX3 was similar or superior to that observed with liposomal amphotericin B or deoxycholate amphotericin B, respectively; (iii) protection was associated with accelerated recovery of lung phagocytic cells and T-helper-1 lymphocytes and concomitant decrease of inflammatory pathology; and (iv) PTX3 potentiated the therapeutic efficacy of suboptimal doses of either antimycotic drug. Together, these data suggest the potential therapeutic use of PTX3 either alone or as an adjunctive therapy in
A. fumigatus
infections.
Dose-Dependent Resorption of Quinine after Intrarectal Administration to Children with Moderate
Plasmodium falciparum
Malaria
Authors: Pussard Eric , Straczek Celine , Kaboré Idrissa , Bicaba Auguste , Balima-Koussoube Tatiana , Bouree Patrice , Barennes Hubert
Published: October 2004

The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria.
Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species
Authors: Credito Kim L. , Appelbaum Peter C.
Published: October 2004

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially
Clostridium
spp. (85 strains tested, including 21 strains of
C. difficile
), with MICs ranging between ≤0.016 and 0.25 μg/ml.
Community-Onset Disease Caused by
Citrobacter freundii
Producing a Novel CTX-M β-Lactamase, CTX-M-30, in Canada
Authors: Abdalhamid Baha , Pitout Johann D. D. , Moland Ellen S. , Hanson Nancy D.
Published: October 2004

Strains of
Citrobacter freundii
intermediate to cefotaxime but sensitive to ceftazidime were isolated from four different patients in Canada. Sequencing of PCR products by use of CTX-M-specific primers revealed a new combination of four amino acid substitutions. This new gene was designated
bla
CTX-M-30
and was encoded on a 3-kb plasmid. The pI of CTX-M-30 was 8.0.
Plasmid-Mediated Carbapenem-Hydrolyzing Enzyme KPC-2 in an
Enterobacter
sp
Authors: Hossain Ashfaque , Ferraro M. J. , Pino R. M. , Dew R. B. , Moland E. S. , Lockhart T. J. , Thomson K. S. , Goering R. V. , Hanson N. D.
Published: October 2004

A strain of an
Enterobacter
sp. with reduced susceptibility to imipenem, which produced a plasmid-mediated class A carbapenem-hydrolyzing enzyme, KPC-2 β-lactamase, was isolated from a patient with sepsis at a Boston hospital. This is the first report of the production of a plasmid-encoded KPC-2 β-lactamase by an
Enterobacter
sp.
Altered Susceptibility of
Candida glabrata
Bloodstream Isolates to Triazoles at Clinically Relevant pH Values: Comparison of the NCCLS M27-A2, Sensititre YeastOne, and Etest Methods
Authors: Pai Manjunath P. , Jones Ariel L.
Published: October 2004

We studied the MICs of triazoles against 15
Candida glabrata
clinical isolates by the NCCLS M27-A2, Sensititre YeastOne, and Etest methods by using media at pHs 6.0, 7.0, and 7.4. Thirteen isolates were less susceptible to triazoles at pH 6.0 and more susceptible to triazoles at pH 7.4 compared to pH 7.0.
Antibiotic Susceptibility in Neonatal Invasive Isolates of
Streptococcus agalactiae
in a 2-Year Nationwide Surveillance Study in Germany
Authors: Fluegge Kirsten , Supper Sven , Siedler Anette , Berner Reinhard
Published: October 2004

The antimicrobial susceptibility of 296 invasive neonatal group B streptococcus isolates from a nationwide 2-year surveillance study in Germany was investigated. All isolates were susceptible to beta-lactams, linezolid, quinupristin-dalfopristin, and vancomycin. Erythromycin and clindamycin resistance was found in 10.1 and 5.7%, respectively. The
ermB
,
ermTR
, or
mefA
gene was detected in all but one of the erythromycin-resistant isolates.
Antimicrobial and Antileishmanial Activities of Hypocrellins A and B
Authors: Ma Guoyi , Khan Shabana I. , Jacob Melissa R. , Tekwani Babu L. , Li Zuqiang , Pasco David S. , Walker Larry A. , Khan Ikhlas A.
Published: October 2004

Hypocrellins A and B were evaluated for in vitro antimicrobial and antileishmanial activities. Hypocrellin A exhibited promising activity against
Candida albicans
and moderate activity against
Staphylococcus aureus
, methicillin-resistant
S. aureus
,
Pseudomonas aeruginosa
, and
Mycobacterium intracellulare
. Hypocrellin B showed weak antimicrobial activities. Hypocrellin A exhibited potent antileishmanial activity, while hypocrellin B was only moderately active. These results of promising antifungal and antileishmanial activity of hypocrellin A may be useful for further structure-activity relationship and in vivo studies.
In Vitro Pharmacodynamic Characteristics of Amphotericin B, Caspofungin, Fluconazole, and Voriconazole against Bloodstream Isolates of Infrequent
Candida
Species from Patients with Hematologic Malignancies
Authors: Di Bonaventura Giovanni , Spedicato Ilaria , Picciani Carla , D'Antonio Domenico , Piccolomini Raffaele
Published: October 2004

Time-kill and postantifungal effect (PAFE) of amphotericin B, caspofungin, fluconazole, and voriconazole were determined against clinical isolates of
Candida guilliermondii
,
Candida kefyr
, and
Candida lusitaniae
. Azoles displayed fungistatic activity and no measurable PAFE, regardless of the concentration tested. Amphotericin B and caspofungin demonstrated concentration-dependent fungicidal activity, although amphotericin B only produced a significant dose-dependent PAFE against all isolates tested.
Evaluation of a Colorimetric Antifungal Susceptibility Test by Using 2,3-Diphenyl-5-Thienyl-(2)-Tetrazolium Chloride
Authors: Shin Jeong Hwan , Choi Jae-Cheol , Lee Jeong Nyeo , Kim Hyung Hoi , Lee Eun Yup , Chang Chulhun Ludgerus
Published: October 2004

A colorimetric antifungal susceptibility test was performed using 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride. Among 24 strains of
Candida
species, no trailing growth was found. In 22 and 20 strains, the MICs obtained in the colorimetric assay were within two dilutions of those obtained by the National Committee for Clinical Laboratory Standards method for ketoconazole and itraconazole, respectively.
Quinolone-Resistant
Haemophilus influenzae
: Determination of Mutant Selection Window for Ciprofloxacin, Garenoxacin, Levofloxacin, and Moxifloxacin
Authors: Li Xinying , Mariano Noriel , Rahal James J. , Urban Carl M. , Drlica Karl
Published: October 2004

Stepwise selection of ciprofloxacin-resistant
Haemophilus influenzae
mutants produced first-, second-, third-, and fourth-step substitutions in GyrA (S84Y), ParC (S84R), GyrA (D88N), and ParC (E88K), respectively. Successive mutations raised the mutant selection window. The wild-type selection window for garenoxacin, levofloxacin, and moxifloxacin was also measured.
SHV-49, a Novel Inhibitor-Resistant β-Lactamase in a Clinical Isolate of
Klebsiella pneumoniae
Authors: Dubois Véronique , Poirel Laurent , Arpin Corinne , Coulange Laure , Bebear Cécile , Nordmann Patrice , Quentin Claudine
Published: October 2004

A clinical strain of
Klebsiella pneumoniae
carried the
bla
SHV-49
gene, encoding a novel inhibitor-resistant β-lactamase of pI 7.6, derived from SHV-1 by the single substitution M69I. It also harbored a gene differing from
bla
SHV-11
by four silent mutations and coding for a penicillinase. Both genes were chromosome located and might represent either a species-specific gene or an acquired resistance gene.
In Vitro Susceptibilities of
Mycoplasma hyopneumoniae
Field Isolates
Authors: Vicca J. , Stakenborg T. , Maes D. , Butaye P. , Peeters J. , de Kruif A. , Haesebrouck F.
Published: October 2004

The in vitro susceptibilities of 21
Mycoplasma hyopneumoniae
field isolates were determined using a broth microdilution technique. One isolate showed acquired resistance to lincomycin, tilmicosin, and tylosin, while five isolates were resistant to flumequine and enrofloxacin. Acquired resistance against these antimicrobials in
M. hyopneumoniae
field isolates was not reported previously.
Decreased Bioavailability of Rifampin and Other Antituberculosis Drugs in Patients with Advanced Human Immunodeficiency Virus Disease
Authors: Gurumurthy Prema , Ramachandran Geetha , Hemanth Kumar A. K. , Rajasekaran S. , Padmapriyadarsini C. , Swaminathan Soumya , Bhagavathy S. , Venkatesan P. , Sekar L. , Mahilmaran A. , Ravichandran N. , Paramesh P.
Published: October 2004

We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.
Activity of Tigecycline (GAR-936) against
Acinetobacter baumannii
Strains, Including Those Resistant to Imipenem
Authors: Pachón-Ibáñez María Eugenia , Jiménez-Mejías Manuel Enrique , Pichardo Cristina , Llanos Ana Cristina , Pachón Jerónimo
Published: October 2004

We determined the in vitro activities of tigecycline and imipenem against 49 isolates of
Acinetobacter baumannii
, including those resistant to imipenem. The MIC at which 50% of the isolates were inhibited (MIC
50
) and the MIC
90
for tigecycline and imipenem were 2 and 2 mg/liter and 32 and 128 mg/liter, respectively, with 92 and 20%, respectively, of the strains being susceptible. Tigecycline did not show bactericidal activity in the time-kill studies (
n
= 9 strains). Imipenem showed bactericidal activity against seven out of nine strains. These in vitro results show that tigecycline has good in vitro bacteriostatic activity against
A. baumannii
, including strains resistant to imipenem.
Pharmacodynamics of Ceftazidime plus the Serine β-Lactamase Inhibitor AM-112 against
Escherichia coli
Containing TEM-1 and CTX-M-1 β-Lactamases
Authors: Bowker Karen E. , Noel Alan R. , Walsh Timothy R. , Rogers Chris A. , MacGowan Alasdair P.
Published: October 2004

A strain of
Escherichia coli
containing TEM-1 and CTX-M-1 was tested in an in vitro pharmacokinetic model against ceftazidime with and without AM-112, a serine β-lactamase inhibitor. Ceftazidime alone was less effective than ceftazidime plus AM-112, and a single dose was more effective than three fractionated doses.
Nonisotopic, Semiautomated
Plasmodium falciparum
Bioassay for Measurement of Antimalarial Drug Levels in Serum or Plasma
Authors: Noedl Harald , Teja-Isavadharm Paktiya , Miller Robert Scott
Published: October 2004

A simple, nonisotopic, semiautomated bioassay for the measurement of antimalarial drug levels in plasma or serum based on the quantitation of histidine-rich protein II in malaria culture is presented. The assay requires only small sample volumes and was found to be highly sensitive and reproducible. The results closely paralleled those obtained with isotopic bioassays (
R
= 0.988,
P
< 0.001) and high-performance liquid chromatography-electrochemical detection (
R
= 0.978,
P
< 0.001).
ZERO MODES IN A SYSTEM OF AHARONOV–BOHM FLUXES
Authors: GEYLER V. A. , ŠŤOVÍČEK P.
Published: October 2004

We study zero modes of two-dimensional Pauli operators with Aharonov–Bohm fluxes in the case when the solenoids are arranged in periodic structures like chains or lattices. We also consider perturbations to such periodic systems which may be infinite and irregular but they are always supposed to be sufficiently scarce.
AN ALGORITHM FOR STEINER TREES IN GRID GRAPHS AND ITS APPLICATION TO HOMOTOPIC ROUTING
Authors: KAUFMANN MICHAEL , GAO SHAODI , THULASIRAMAN K.
Published: October 2004

In this paper we present an algorithm for Steiner minimal trees in grid graphs with all terminals located on the boundary of the graph. The algorithm runs in O(min{k4, k2n}) time, where k and n are the numbers of terminals and vertices of the graph, respectively. It can handle non-convex boundaries and is the fastest known for this case. We also consider the homotopic routing problem and apply our Steiner tree algorithm to construct minimum-length wires for multi-terminal nets.
A NEW METHOD FOR SC CIRCUIT SYNTHESIS BASED ON THE VOLTAGE INVERSION CONCEPT
Authors: DELIYANNIS T. , HARITANTIS I. , ALEXIOU G. , PSYCHALINOS C. , LIMPERIS A. , LAYOS M.
Published: October 2004

A new general method for SC circuit synthesis, based on the voltage inversion concept, is presented. According to the proposed method, first- and second-order SC equivalent admittances are developed and subsequently a number of SC subcircuits are derived. These subcircuits are used in the derivation of high order filters. Emphasis is given to integrator and second-order circuits. All the proposed circuits are fully parasitics free and compare favourably with known circuits. Two design examples of high order filters are also given. One of them was further designed in an IC form.
IMPROVED MICROWAVE SELECTIVE DEVICES USING WEAKLY ASYMMETRIC RESONANT CAVITIES
Authors: MANOLACHE FLORIN BOGDAN , SANDU DUMITRU D. , COSTINER SORIN
Published: October 2004

Microwave selective devices using localized close frequency modes in weakly asymmetric resonant cavities (WARC) are introduced. The splitting, coupling and resonant structures of the new microwave filters are integrated in a single cavity. Therefore, the signal losses are reduced and the selectivity is improved. The utilization of localized modes is a general new principle which raises the efficiency of a class of microwave selective devices.
MATHEMATICAL MODELLING OF AN AUTOMATIC VOLTAGE REGULATOR
Authors: GREGORY K. , SMITH I.R.
Published: October 2004

This letter describes the mathematical modelling of an automatic voltage regulator (avr) in a form which is compatible with models developed for many other items of electrical plant. The corresponding equations are suitable for numerical solution on a digital computer, and results are presented to illustrate the performance when the avr program is added to an existing generator program to produce an overall system model.
AN ELECTRICAL ANALOGUE FOR A GEAR BOX
Authors: GREGORY K. , SMITH I.R.
Published: October 2004

This letter outlines an electrical analogue for a gearbox, which is suitable for use in the modelling of many electromechanical systems. Unlike existing models it is compatible with conventional models for the electrical items of a system, and allows for the effect of backlash on these other items.
A DIGITAL PERCEPTRON LEARNING IMPLEMENTATION WITH LOOK-UP TABLE FEEDBACK LAYER
Authors: ZHANG D. , ELMASRY M.I.
Published: October 2004

In this paper, a digital perceptron learning structure using a priori knowledge inherent in layered networks is presented. Its implementation mechanism is accompanied by the corresponding look-up table technology in VLSI medium. Compared with the conventional learning algorithm, it is shown that this structure can reduce the complexity of implementation in VLSI while maintaining the same performance.
A MULTIPROCESSOR NETWORK ARRANGING REPLICATED OBJECTS IN PAIRWISE BALANCED COMBINATORIAL DESIGNS
Authors: BERKOVICH SIMON Y. , CHANG LIN-CHING
Published: October 2004

The paper investigates a new type of computer interconnection structure using a combinatorial arrangement with pairwise balanced design property in which the interconnection is organized through replication of corresponding objects. The suggested system provides low access latency and reduces the communication overhead. A simulation study to evaluate the performance of this system is presented. The considered organization provides a direct support of object-oriented constructs in distributed systems.
PERTURBATION TECHNIQUES FOR ON-CHIP LEARNING WITH ANALOGUE VLSI MLPs
Authors: CAIRNS GRAHAM , TARASSENKO LIONEL
Published: October 2004

Microelectronic neural network technology has become sufficiently mature over the past few years that reliable performance can now be obtained from VLSI circuits under carefully controlled conditions (see Refs. 8 or 13 for example). The use of analogue VLSI allows low power, area efficient hardware realisations which can perform the computationally intensive feed-forward operation of neural networks at high speed, making real-time applications possible.

In this paper we focus on important issues for the successful operation and implementation of on-chip learning with such analogue VLSI neural hardware, in particular the issue of weight precision. We first review several perturbation techniques which have been proposed to train multi-layer perceptron (MLP) networks. We then present a novel error criterion which performs well on benchmark problems and which allows simple integration of error measurement hardware for complete on-chip learning systems.
IMPLEMENTATION AND EXPERIMENTAL RESULTS OF A CHIP FOR THE SEPARATION OF MIXED AND FILTERED SIGNALS
Authors: GHARBI AMMAR B.A. , SALAM FATHI M.A.
Published: October 2004

We describe an algorithm and chip implementation for separating a mixture of unknown, but independent, temporal signals in static and dynamic environments. The proposed algorithm, which is a simple modification of the Herault and Jutten (HJ) algorithm, proved to be robust to parameter variations in both cases. We present chip test results to quantify the performance of the modified algorithm in static and dynamic (mixing and filtering) environments. Moreover, experiments of separating two speech or two music signals in English-English, English-Japanese, and English-Arabic have demonstrated successful performance.
AN ADAPTIVE NOISE CANCELER IMPLEMENTED WITH CMOS ANALOG TECHNOLOGY
Authors: GOMEZ GABRIEL , SIFERD RAYMOND
Published: October 2004

A fully analog implementation of an adaptive noise canceler is presented, including design, simulation, and test results of the fabricated chip. The prototype chip was fabricated using 2-µ CMOS P-Well technology on a 4.0 mm2 die and uses ±5 V power supplies. The static power dissipation is 276 milliwatts. Analog signal processing techniques are used to realize an adaptive system based upon a finite impulse response (FIR) filter and least mean squares (LMS) adaptive algorithm. The circuit is tested as an adaptive noise canceler, where a signal corrupted by noise is the input. The circuit adaptively converges to cancel the noise to produce an output that is the best LMS estimate of the signal. The circuit could be used for other real-time adaptive filter applications or for realizing an on-chip learning algorithm. The implementation illustrates the advantages of an analog system with no requirements for A/D and D/A converters, reduced size of circuit subsystems (e.g. multipliers), and the relatively fast convergence.
AN ELECTRONIC HABITUATION CHIP
Authors: WANG TONY , AKERS L.A.
Published: October 2004

Habituation is a biological behavior allowing non-critical information to be disregarded enabling more processing resources for critical tasks. This requires the ability to determine if a signal is novel or not. We have implemented habituation adaptation in a small mixed signal circuit. A software simulation is used to demonstrate the ability of habituation to eliminate a stuck-at 1 error from succeeding stages of processing. Experimental test results are shown illustrating the habituation response.
CMOS IMPLEMENTATION OF A VOLTAGE-MODE FUZZY MIN-MAX CONTROLLER
Authors: OTA Y. , WILAMOWSKI B.M.
Published: October 2004

In this paper, a general-purpose fuzzy min-max network using a Gaussian-type membership function fuzzifier is proposed. Particularly, CMOS implementations of the Gaussian-type membership function fuzzifier circuits, min-max operators, and the defuzzifier circuit are analyzed. Programmability of the proposed Gaussian-type function fuzzifier can be achieved by changing the gate voltages and the sizes of transistors in the differential pairs. A closed-loop control scheme is used between the fuzzifier and defuzzifier blocks to compensate the global normalization of the denominator in the division of a centroid calculation in the defuzzifier block.
MATRIX PENCIL METHODS FOR 2-D FREQUENCY ESTIMATION
Authors: BAQAI FARHAN A. , HUA YINGBO , YANG HUA
Published: October 2004

The problem of estimating two-dimensional frequencies of multiple sinusoids embedded in noise is addressed. A variant of the recently reported matrix pencil method is proposed. Numerical results that provide insights into the perturbation deviations of the estimated two-dimensional frequencies are given for both methods. The variant method is shown to be computationally much more efficient than the original method while their accuracies are comparable.
STATE FEEDBACK FILTERS
Authors: OKSASOGLU ALI , HUELSMAN LAWRENCE P.
Published: October 2004

This paper introduces the development of a new active analog filter realization, namely the state feedback filter, and presents an implementation and design procedure utilizing the idea of the state feedback technique. The effects of gain bandwidth on the performance of the state feedback realizations with respect to properties, such as, magnitude and phase characteristics are investigated and discussed.
TASK ASSIGNMENT IN HOST-SATELLITE SYSTEMS
Authors: SEO KYUNG-RYONG , PARK KYU-HO
Published: October 2004

This paper deals with the problem of assigning task modules of a program over a multiple computer system such that the sum of execution and communication costs is minimized. If the number of processors is two, this problem can be solved efficiently using the network flow approach pioneered by Stone.13 However, the general n-processor problem (n>3) in a fully connected system is known to be NP-complete.14

A host-satellite system considered in this paper is composed of a powerful host processor p0 and N homogeneous satellite processors pk’s, 1≤k≤N, in which each satellite processor pk is connected to the host processor p0 through a communication link. When any two satellite processors are to communicate with each other, the host processor p0 must participate in the communication. Therefore, the interprocessor communication cost per unit of information transferred between any two satellite processors is twice as much as that between a satellite processor and the host processor p0.

In this paper, we propose an algorithm which finds an optimal assignment on a host-satellite system in polynomial time. A task assignment problem for a host-satellite system is first transformed into a network flow problem, and then solved by applying the well known network flow algorithm in time no worse than O(NM3), where N and M are the number of satellites and the number of modules, respectively.
TRANSFORMATION OF NESTED LOOPS INTO UNIFORM RECURRENCES AND THEIR MAPPING TO REGULAR PROCESSOR ARRAYS
Authors: KYRIAKIS-BITZAROS E.D. , SOUDRIS D.J. , GOUTIS C.E.
Published: October 2004

A methodology for transforming a class of iterative algorithms, expressed in nested loops, into Uniform Recurrent Equation (URE) forms and their mapping into regular processor array architectures is presented. The propagation space of the variables of the original nested loop is specified by a system of linear equations formed by their index functions. The data flow within the index space, is then localized by the derivation of a set of parametric dependence vectors, which eventually can be used to transform the initial algorithm into a set of UREs. The mapping of the UREs is accomplished by decomposition of the index space into independent subsets of variable instances using the derived dependence vectors. The dependence graphs of the subsets are normalized and subsequently, are mapped on the processor array architecture. The exploitation of the independent subsets leads to significant improvement of the efficiency of the processor array compared to architectures derived by using linear transformations of the entire index space. Under certain conditions, only local interconnections in the processor array are required. The proposed methodology is illustrated by the design of alternative processor arrays implementing the convolution algorithm.
NONRESTORING RADIX-2k SQUARE ROOTING ALGORITHM
Authors: BASHAGHA A.E. , IBRAHIM M.K.
Published: October 2004

This paper presents a new high radix square rooting algorithm where a number of square root bits (one digit) are generated in one step. Therefore, the proposed algorithm offers a higher speed than that of the conventional bit parallel binary one. This algorithm can be considered as a generalisation of the conventional bit parallel binary algorithm, and therefore it can be implemented using the existing simple binary elements. The proposed algorithm makes use only of the odd values of the square root to generate the possible values of the radicand and therefore, it requires less area than the conventional restoring high radix algorithm which uses all the values of the square root. This algorithm is general for any radix. Any adder can be used in the basic cell, it can be a carry ripple adder or a carry lookahead adder. As an example of a radix-2k square root architecture, a 9-bit radix-23 architecture is presented in this paper.
A UNIFIED ALGORITHM FOR THE ESTIMATION AND SCHEDULING OF DATA FLOW GRAPHS
Authors: HU YUAN , CARLSON BRADLEY S.
Published: October 2004

A unified algorithm is presented to solve the problem of estimation and scheduling for performance constrained data flow graphs. The algorithm achieves superior results by first computing a lower bound on the number of functional units required to satisfy the performance constraint T, and then scheduling the operations into the best control steps using the lower bound algorithm. The lower bound not only greatly reduces the size of the solution space, but also provides a means to measure the proximity of the final solution to an optimal one. Our algorithm is the first one to use a sharp lower bound estimation technique to direct scheduling. In addition, our unified algorithm can easily be incorporated into a branch-and-bound algorithm to solve the scheduling problem optimally. Since our algorithm computes a sharp lower bound, the computation time of an optimal algorithm can be greatly reduced. Experiments indicate that our scheduling algorithm can produce results very close to the lower bound. For all of the test cases the difference between our upper and lower bounds is not greater than one.