bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control of Impact Microactuators for Precise Positioning
Authors: Zhao Xiaopeng , Dankowicz Harry 
Published: March 2007

Abstract
Electrically driven impact microactuators generate nanoscale displacements without large driving distances and high voltages. These systems exhibit complex dynamics because of inherent nonlinearities due to impacts, friction, and electric forces. As a result, dramatic changes in system behavior, associated with so-called grazing bifurcations, may occur during the transition between impacting and nonimpacting dynamics, including the presence of robust chaos. For successful open-loop operating conditions, the system design is limited to certain parameter regions, where desired system responses reside. The objective of this paper is to overcome this limitation to allow for a more precise displacement manipulation using impact microactuators. This is achieved through a closed-loop feedback scheme that successfully controls the system dynamics in the near-grazing region.
Longitudinally Tracking Fluoroquinolone Resistance and Its Determinants in Penicillin-Susceptible and -Nonsusceptible
Streptococcus pneumoniae
Isolates in Hong Kong, 2000 to 2005
Authors: Ip Margaret , Chau Shirley S. L. , Chi Fang , Cheuk Edmund S. C. , Ma Helen , Lai Raymond W. M. , Chan Paul K. 
Published: March 2007

ABSTRACT

Of 1,388
Streptococcus pneumoniae
isolates collected from 2000 to 2005, 10.5% had a ciprofloxacin MIC of ≥4.0 μg/ml and 1.6% (range, 0.8% to 4.3% per year) had a levofloxacin MIC of ≥4.0 μg/ml. Molecular characterization indicated that fluoroquinolone resistance occurred independently in our prevalent Spain
23F
-1 clone, expressing serotypes 23F, 19F, and 14. Rates of resistance to levofloxacin in
S. pneumoniae
have remained stable at a Hong Kong hospital.
Mutations in 16S rRNA and Ribosomal Protein S5 Associated with High-Level Spectinomycin Resistance in
Pasteurella multocida
Authors: Kehrenberg Corinna , Schwarz Stefan 
Published: March 2007

ABSTRACT

Pasteurella multocida
isolates with high-level spectinomycin resistance in which no adenyltransferase genes could be demonstrated exhibited a C1192G transversion in the 16S rRNA of all six or five of the six rRNA operons and/or two different types of 3-bp deletions in the
rpsE
gene that codes for the ribosomal protein S5.
High-Level Gentamicin Resistance Mediated by a Tn
4001
-Like Transposon in Seven Nonclonal Hospital Isolates of
Streptococcus pasteurianus
Authors: Chow Viola C. Y. , Hawkey Peter M. , Chan Edward W. C. , Chin Miu L. , Au T. K. , Fung Danny K. C. , Chan Raphael C. Y. 
Published: March 2007

ABSTRACT

We report on the first occurrence of high-level gentamicin resistance (MICs ≥ 512 μg/ml) in seven clinical isolates of
Streptococcus pasteurianus
from Hong Kong. These seven isolates were confirmed to be the species
S. pasteurianus
on the basis of nucleotide sequencing of the superoxide dismutase (
sodA
) gene. Epidemiological data as well as the results of pulse-field gel electrophoresis analysis suggested that the seven
S. pasteurianus
isolates did not belong to the same clone. Molecular characterization showed that they carried a chromosomal, transposon-borne resistance gene [
aac(6′)Ie-aph(2″)Ia
] which was known to encode a bifunctional aminoglycoside-modifying enzyme. The genetic arrangement of this transposon was similar to that of Tn
4001
, a transposon previously recovered from
Staphylococcus aureus
and other gram-positive isolates. Genetic linkage with other resistance elements, such as the
ermB
gene for erythromycin resistance, was not evident. On the basis of these findings, we suggest that routine screening for high-level gentamicin resistance should be recommended for all clinically significant blood culture isolates. This is to avoid the inadvertent use of short-course combination therapy with penicillin and gentamicin, which may lead to the failure of treatment for endocarditis, the selection of drug-resistant
Streptococcus pasteurianus
and other gram-positive organisms, as well as the unnecessary usage of gentamicin, a drug with potential toxicity.
Daptomycin Produces an Enhanced Bactericidal Activity Compared to Ceftriaxone, Measured by [
3
H]Choline Release in the Cerebrospinal Fluid, in Experimental Meningitis Due to a Penicillin-Resistant Pneumococcal Strain without Lysing Its Cell Wall
Authors: Stucki A. , Cottagnoud M. , Winkelmann V. , Schaffner T. , Cottagnoud P. 
Published: March 2007

ABSTRACT

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [
3
H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.
Prevention of Brain Injury by the Nonbacteriolytic Antibiotic Daptomycin in Experimental Pneumococcal Meningitis
Authors: Grandgirard Denis , Schürch Christian , Cottagnoud Philippe , Leib Stephen L. 
Published: March 2007

ABSTRACT

Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 × 10
4
± 0.5 × 10
4
CFU of
Streptococcus pneumoniae
serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.];
n
= 55) or daptomycin (50 mg/kg s.c.;
n
= 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log
10
3.6 ± 1.0 and log
10
6.3 ± 1.4 CFU/ml, respectively;
P
< 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (
P
< 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively;
P
< 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.
A New
Aspergillus fumigatus
Resistance Mechanism Conferring In Vitro Cross-Resistance to Azole Antifungals Involves a Combination of
cyp51A
Alterations
Authors: Mellado E. , Garcia-Effron G. , Alcázar-Fuoli L. , Melchers W. J. G. , Verweij P. E. , Cuenca-Estrella M. , Rodríguez-Tudela J. L. 
Published: March 2007

ABSTRACT

Fourteen
Aspergillus fumigatus
clinical isolates that exhibited a pattern of reduced susceptibility to triazole drugs were analyzed. The sequences of the
cyp51A
gene from all isolates showed the presence of a point mutation at t364a, which led to the substitution of leucine 98 for histidine (L98H), together with the presence of two copies of a 34-bp sequence in tandem in the promoter of the
cyp51A
gene. Quantitative expression analysis (real-time PCR) showed up to an eightfold increase in the level of expression of the
cyp51A
gene compared to that by the susceptible strain. Three PCR fragments of one azole-resistant strain (strain CM2627) that included the promoter with the tandem repeat and part of
cyp51
A with the t364a mutation or PCR fragments with only one of the modifications were used to replace the
cyp51A
gene of an azole drug-susceptible
A. fumigatus
wild-type strain (strain CM237). Only transformants which had incorporated the tandem repeat in the promoter of the
cyp51A
gene and the L98H amino acid substitution exhibited similarly reduced patterns of susceptibility to all triazole agents and similarly increased levels of
cyp51A
expression, confirming that the combination of both alterations was responsible for the azole-resistant phenotype.
Treatment of
Staphylococcus aureus
Biofilm Infection by the Quorum-Sensing Inhibitor RIP
Authors: Balaban Naomi , Cirioni Oscar , Giacometti Andrea , Ghiselli Roberto , Braunstein Joel B. , Silvestri Carmela , Mocchegiani Federico , Saba Vittorio , Scalise Giorgio 
Published: March 2007

ABSTRACT

The quorum-sensing inhibitor RIP inhibits staphylococcal TRAP/
agr
systems and both TRAP- and
agr
-negative strains are deficient in biofilm formation in vivo, indicating the importance of quorum sensing to biofilms in the host. RIP injected systemically into rats has been found to have strong activity in preventing methicillin-resistant
Staphylococcus aureus
graft infections, suggesting that RIP can be used as a therapeutic agent.
Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients
Authors: Marin-Niebla Ana , Lopez-Cortes Luis Fernando , Ruiz-Valderas Rosa , Viciana Pompeyo , Mata Rosario , Gutierrez Alicia , Pascual Rosario , Rodriguez Magdalena 
Published: March 2007

ABSTRACTWe evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10copies/ml. MedianCmax, area under the concentration-time curve from 0 to 24 h, andCminplasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequateCminlevels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.
Spread of Extended-Spectrum β-Lactamase CTX-M-Producing
Escherichia coli
Clinical Isolates in Community and Nosocomial Environments in Portugal
Authors: Mendonça Nuno , Leitão Joana , Manageiro Vera , Ferreira Eugénia , Caniça Manuela 
Published: March 2007

ABSTRACT

Of the 181 unduplicated
Escherichia coli
strains isolated in nine different hospitals in three Portuguese regions, 119 were extended-spectrum β-lactamase (ESBL)-CTX-M producers and were selected for phenotype and genotype characterization. CTX-M producer strains were prevalent among community-acquired infections (56%), urinary tract infections (76%), and patients ≥60 years old (76%). In MIC tests, all strains were resistant to cefotaxime, 92% were resistant to ceftazidime, 93% were resistant to quinolones, 89% were resistant to aminoglycoside, and 26% were resistant to trimethoprim-sulfamethoxazole; all strains were sensitive to carbapenems, and 92% of the strains had a multidrug resistance phenotype. Molecular methods identified 109 isolates harboring a
bla
CTX-M-15
gene, 1 harboring the
bla
CTX-M-32
gene (first identification in the country), and 9 harboring the
bla
CTX-M-14
gene. All isolates presented the IS
Ecp1
element upstream from the
bla
CTX-M
genes; one presented the IS
903
element (downstream of
bla
CTX-M-14
gene), and none had the IS
26
element; 85% carried
bla
TEM-1B
, and 84% also carried a
bla
OXA-30
. Genetic relatedness analysis based on pulsed-field gel electrophoresis defined five clusters and indicated that 76% of all isolates (from cluster IV) corresponded to a single epidemic strain. Of the 47 strains from one hospital, 41 belonged to cluster IV and were disseminated in three main wards. CTX-M-producing
E. coli
strains are currently a problem in Portugal, with CTX-M-15 particularly common. This study suggests that the horizontal transfer of
bla
CTX-M
genes, mediated by plasmids and/or mobile elements, contributes to the dissemination of CTX-M enzymes to community and hospital environments. The use of extended-spectrum cephalosporins, quinolones, and aminoglycosides is compromised, leaving carbapenems as the therapeutic option for severe infections caused by ESBL producers.
A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro
Authors: Amano Masayuki , Koh Yasuhiro , Das Debananda , Li Jianfeng , Leschenko Sofiya , Wang Yuan-Fang , Boross Peter I. , Weber Irene T. , Ghosh Arun K. , Mitsuya Hiroaki 
Published: March 2007

ABSTRACT

We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(
R
),3a(
S
),6a(
R
)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC
50
], 0.0002 to 0.0005 μM) with minimal cytotoxicity (50% cytotoxicity, 35.7 μM in CD4
+
MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1
NL4-3
variants exposed to and selected by up to a 5 μM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 μM concentration of lopinavir or atazanavir (EC
50
, 0.0015 to 0.0075 μM), although it was less active against HIV-1
NL4-3
selected by amprenavir (EC
50
, 0.032 μM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.
Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro
Authors: Caffrey Conor R. , Steverding Dietmar , Swenerton Ryan K. , Kelly Ben , Walshe Deirdre , Debnath Anjan , Zhou Yuan-Min , Doyle Patricia S. , Fafarman Aaron T. , Zorn Julie A. , Land Kirkwood M. , Beauchene Jessica , Schreiber Kimberly , Moll Heidrun , Ponte-Sucre Alicia , Schirmeister Tanja , Saravanamuthu Ahilan , Fairlamb Alan H. , Cohen Fred E. , McKerrow James H. , Weisman Jennifer L. , May Barnaby C. H. 
Published: March 2007

ABSTRACTParasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC50) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC50values againstPlasmodium falciparumandTrypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent ofP. falciparumresistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent useful starting points for further lead optimization.
In Vitro Activity of 2,4-Diamino-6-[2-(Phosphonomethoxy)Ethoxy]-Pyrimidine against Multidrug-Resistant Hepatitis B Virus Mutants
Authors: Brunelle M. N. , Lucifora J. , Neyts J. , Villet S. , Holy A. , Trepo C. , Zoulim F. 
Published: March 2007

ABSTRACTThe susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
Staphylococcus aureus
Strains That are Hypersusceptible to Resistance Gene Transfer from Enterococci
Authors: Sung Julia M.-L. , Lindsay Jodi A. 
Published: March 2007

ABSTRACT

We identified naturally occurring
Staphylococcus aureus
mutants of the restriction modification pathway SauI, including bovine lineage ST151. In a model of vancomycin resistance transfer from
Enterococcus faecalis
, ST151 isolates are 500 times more susceptible than human
S. aureus
isolates. The eradication of “hyperrecipient” strains may reduce the evolution of vancomycin-resistant
S. aureus
.
Kinetic Characterization of Squalene Synthase fromTrypanosoma cruzi: Selective Inhibition by Quinuclidine Derivatives
Authors: Sealey-Cardona Marco , Cammerer Simon , Jones Simon , Ruiz-Pérez Luis M. , Brun Reto , Gilbert Ian H. , Urbina Julio A. , González-Pacanowska Dolores 
Published: March 2007

ABSTRACTThe biosynthesis of sterols is a major route for the development of antitrypanosomals. Squalene synthase (SQS) catalyzes the first step committed to the biosynthesis of sterols within the isoprenoid pathway, and several inhibitors of the enzyme have selective antitrypanosomal activity both in vivo and in vitro. The enzyme fromTrypanosoma cruziis a 404-amino-acid protein with a clearly identifiable membrane-spanning region. In an effort to generate soluble recombinant enzyme, we have expressed inEscherichia coliseveral truncated versions ofT. cruziSQS with a His tag attached to the amino terminus. Deletions of both the amino- and carboxyl-terminal regions generated active and soluble forms of the enzyme. The highest levels of soluble protein were achieved when 24 and 36 amino acids were eliminated from the amino and carboxyl regions, respectively, yielding a protein of 41.67 kDa. The Michaelis-Menten constants of the purified enzyme for farnesyl diphosphate and NAD (NADPH) were 5.25 and 23.34 μM, respectively, whereas theVmaxwas 1,428.56 nmol min−1mg−1. Several quinuclidine derivatives with antiprotozoal activity in vitro were found to be selective inhibitors of recombinantT. cruzi SQS in comparative assays with the human enzyme, with 50% inhibitory concentration values in the nanomolar range. These data suggest that selective inhibition ofT. cruziSQS may be an efficient strategy for the development of new antitrypanosomal agents.
Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates
Authors: Metsvaht Tuuli , Oselin Kersti , Ilmoja Mari-Liis , Anier Kaili , Lutsar Irja 
Published: March 2007

ABSTRACT

Data on the pharmacokinetics (PKs) of penicillin G (PEN) in neonates date back to the 1970s and do not include data for very-low-birth-weight (VLBW) neonates. The aim of this study was to describe the steady-state PKs and to establish an optimal regimen for the dosing of PEN in neonates with gestational ages of less than 28 weeks and birth weights of less than 1,200 g. Two PEN dosing regimens were studied: 50,000 IU (30 mg)/kg of body weight every 12 h (q12h) (group 1;
n
= 9) and 25,000 IU (15 mg)/kg q12h (group 2;
n
= 9). Samples for PK analysis were drawn before the injection of PEN and at 2 and 30 min and 1.5, 4, 8, and 12 h after intravenous injection of the third to eighth PEN doses. The PEN concentration was measured by a high-performance liquid chromatography with UV detection technique. The median peak and trough concentrations of PEN were 147 μg/ml (lower and upper quartiles, 109 and 157 μg/ml, respectively) and 7 μg/ml (lower and upper quartiles, 5 and 13 μg/ml, respectively) after administration of the dose of 50,000 IU and 59 μg/ml (lower and upper quartiles, 53 and 78 μg/ml, respectively) and 3 μg/ml (lower and upper quartiles, 3 and 4 μg/ml, respectively) after administration of the dose of 25,000 IU. The PEN half-life (median and lower and upper quartiles for group 1, 3.9 h and 3.3 and 7.0 h, respectively; median and lower and upper quartiles for group 2, 4.6 h and 3.8 and 5.6 h, respectively) was longer in VLBW neonates than in adults and term infants. PEN renal clearance correlated with creatinine clearance (
R
2
= 0.309596;
P
= 0.038). Only a median of 34% (lower and upper quartiles, 28 and 37%, respectively) of the administered dose was excreted in urine within the following 12 h. We conclude that in VLBW infants a PEN dose of 25,000 IU (15 mg)/kg q12h is safe and sufficient to achieve serum concentrations above the MIC
90
for group B streptococci for the entire dosing interval.