bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Instant Center Approach Toward the Conceptual Design of Compliant Mechanisms
Authors: Kim Charles J. , Kota Sridhar , Moon Yong-Mo 
Published: March 2006

Abstract
As with conventional mechanisms, the conceptual design of compliant mechanisms is a blend of art and science. It is generally performed using one of two methods: topology optimization or the pseudo-rigid-body model. In this paper, we present a new conceptual design methodology which utilizes a building block approach for compliant mechanisms performing displacement amplification/attenuation. This approach provides an interactive, intuitive, and systematic methodology for generating initial compliant mechanism designs. The instant center is used as a tool to construct the building blocks. The compliant four-bar building block and the compliant dyad building block are presented as base mechanisms for the conceptual design. It is found that it is always possible to obtain a solution for the geometric advantage problem with an appropriate combination of these building blocks. In a building block synthesis, a problem is first evaluated to determine if any known building blocks can satisfy the design specifications. If there are none, the problem is decomposed to a number of sub-problems which may be solved with the building blocks. In this paper, the problem is decomposed by selecting a point in the design space where the output of the first building block coincides with the second building block. Two quantities are presented as tools to aid in the determination of the mechanism's geometry – (i) an index relating the geometric advantage of individual building blocks to the target geometric advantage and (ii) the error in the geometric advantage predicted by instant centers compared to the calculated value from FEA. These quantities guide the user in the selection of the location of nodes of the mechanism. Determination of specific cross-sectional size is reserved for subsequent optimization. An example problem is provided to demonstrate the methodology's capacity to obtain good initial designs in a straightforward manner. A size and geometry optimization is performed to demonstrate the viability of the design.
Maribavir Pharmacokinetics and the Effects of Multiple-Dose Maribavir on Cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A,
N
-Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults
Authors: Ma Joseph D. , Nafziger Anne N. , Villano Stephen A. , Gaedigk Andrea , Bertino Joseph S. 
Published: March 2006

ABSTRACT

Maribavir (1263W94, VP-41263) is an oral anticytomegalovirus agent under clinical development. The pharmacokinetics and safety of maribavir and the effects of maribavir on the activities of cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A,
N
-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) were evaluated in a randomized, double-blind, placebo-controlled study. Twenty healthy subjects received a five-drug phenotyping cocktail of caffeine (CYP 1A2, NAT-2, XO), warfarin plus vitamin K (CYP 2C9), omeprazole (CYP 2C19), dextromethorphan (CYP 2D6), and midazolam (CYP 3A) 4 days before and after 7 days of treatment with maribavir at 400 mg twice daily (16 subjects) or placebo (4 subjects) for 10 days. Maribavir did not affect the CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO activities. Bioequivalence was not demonstrated for CYP 2C19 and CYP 2D6, suggesting a decrease or inhibition of CYP 2C19 and CYP 2D6 activities. The pharmacokinetics of maribavir following a single dose and after 10 days of treatment were similar, with minimal accumulation at steady state. Maribavir was safe and well tolerated. Taste disturbance was the most frequently reported adverse event. These results will further guide evaluation of the drug interaction potential and clinical development of maribavir.
Garenoxacin Treatment of Experimental Endocarditis Caused by Viridans Group Streptococci
Authors: Anguita-Alonso Paloma , Rouse Mark S. , Piper Kerryl E. , Steckelberg James M. , Patel Robin 
Published: March 2006

ABSTRACT

The activity of garenoxacin was compared to that of levofloxacin or penicillin in a rabbit model of
Streptococcus mitis
group (penicillin MIC, 0.125 μg/ml) and
Streptococcus sanguinis
group (penicillin MIC, 0.25 μg/ml) endocarditis. Garenoxacin and levofloxacin had MICs of 0.125 and 0.5 μg/ml, respectively, for both study isolates. Rabbits with catheter-induced aortic valve endocarditis were given no treatment, penicillin at 1.2 × 10
6
IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously. For both isolates tested, garenoxacin area under the curve (AUC)/MIC and maximum concentration of drug in serum (
C
max
)/MIC ratios were 368 and 91, respectively. Rabbits were sacrificed after 3 days of treatment; cardiac valve vegetations were aseptically removed and quantitatively cultured. For
S. mitis
group experimental endocarditis, all studied antimicrobial agents were more active than no treatment (
P
< 0.001), whereas for
S. sanguinis
group endocarditis, no studied antimicrobial agents were more active than no treatment. We conclude that AUC/MIC and
C
max
/MIC ratios may not predict activity of some quinolones in experimental viridans group endocarditis and that garenoxacin and levofloxacin may not be ideal choices for serious infections caused by some quinolone-susceptible viridans group streptococci.
Using Bacteriophages To Reduce Formation of Catheter-Associated Biofilms byStaphylococcus epidermidis
Authors: Curtin John J. , Donlan Rodney M. 
Published: March 2006

ABSTRACTUse of indwelling catheters is often compromised as a result of biofilm formation. This study investigated if hydrogel-coated catheters pretreated with a coagulase-negative bacteriophage would reduceStaphylococcus epidermidisbiofilm formation. Biofilms were developed on hydrogel-coated silicone catheters installed in a modified drip flow reactor. Catheter segments were pretreated with the lyticS. epidermidisbacteriophage 456 by exposing the catheter lumen to a 10-log-PFU/ml culture of the bacteriophage for 1 h at 37°C prior to biofilm formation. The untreated mean biofilm cell count was 7.01 ± 0.47 log CFU/cm2of catheter. Bacteriophage treatment with and without supplemental divalent cations resulted in log-CFU/cm2reductions of 4.47 (P< 0.0001) and 2.34 (P= 0.001), respectively. Divalent cation supplementation without bacteriophage treatment provided a 0.67-log-CFU/cm2reduction (P= 0.053). Treatment of hydrogel-coated silicone catheters with anS. epidermidisbacteriophage in an in vitro model system significantly reduced viable biofilm formation byS. epidermidisover a 24-h exposure period, suggesting the potential of bacteriophage for mitigating biofilm formation on indwelling catheters and reducing the incidence of catheter-related infections.
Triaryl Pyrazoline Compound Inhibits Flavivirus RNA Replication
Authors: Puig-Basagoiti Francesc , Tilgner Mark , Forshey Brett M. , Philpott Sean M. , Espina Noel G. , Wentworth David E. , Goebel Scott J. , Masters Paul S. , Falgout Barry , Ren Ping , Ferguson David M. , Shi Pei-Yong 
Published: March 2006

ABSTRACTTriaryl pyrazoline {[5-(4-chloro-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-phenyl-methanone} inhibits flavivirus infection in cell culture. The inhibitor was identified through high-throughput screening of a compound library using a luciferase-expressing West Nile (WN) virus infection assay. The compound inhibited an epidemic strain of WN virus without detectable cytotoxicity (a 50% effective concentration of 28 μM and a compound concentration of ≥300 μM required to reduce 50% cell viability). Besides WN virus, the compound also inhibited other flaviviruses (dengue, yellow fever, and St. Louis encephalitis viruses), an alphavirus (Western equine encephalitis virus), a coronavirus (mouse hepatitis virus), and a rhabdovirus (vesicular stomatitis virus). However, the compound did not suppress an orthomyxovirus (influenza virus) or a retrovirus (human immunodeficiency virus type 1). Mode-of-action analyses in WN virus showed that the compound did not inhibit viral entry or virion assembly but specifically suppressed viral RNA synthesis. To examine the mechanism of inhibition of dengue virus, we developed two replicon systems for dengue type 1 virus: (i) a stable cell line that harbored replicons containing a luciferase reporter and a neomycin phosphotransferase selection marker and (ii) a luciferase-expressing replicon that could differentiate between viral translation and RNA replication. Analyses of the compound in the dengue type 1 virus replicon systems showed that it weakly suppressed viral translation but significantly inhibited viral RNA synthesis. Overall, the results demonstrate that triaryl pyrazoline exerts a broad spectrum of antiflavivirus activity through potent inhibition of viral RNA replication. This novel inhibitor could be developed for potential treatment of flavivirus infection.
Activity and Mechanism of Action of
N
-Methanocarbathymidine against Herpesvirus and Orthopoxvirus Infections
Authors: Prichard Mark N. , Keith Kathy A. , Quenelle Debra C. , Kern Earl R. 
Published: March 2006

ABSTRACT

N
-Methanocarbathymidine [(
N
)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes simplex virus and also appears to be dependent on the type II TK expressed by cowpox and vaccinia viruses, suggesting that it is a substrate for both of these divergent forms of the enzyme. The drug is also a good inhibitor of viral DNA synthesis in both viruses and is consistent with inhibition of the viral DNA polymerase once it is activated by the viral TK homologs. This mechanism of action explains the rather unusual spectrum of activity, which is limited to orthopoxviruses, alphaherpesviruses, and Epstein-Barr virus, since these viruses express molecules with TK activity that can phosphorylate and thus activate the drug. The compound is also effective in vivo and reduces the mortality of mice infected with orthopoxviruses, as well as those infected with herpes simplex virus type 1 when treatment is initiated 24 h after infection. These results indicate that (
N
)-MCT is active in vitro and in vivo, and its mechanism of action suggests that the molecule may be an effective therapeutic for orthopoxvirus and herpesvirus infections, thus warranting further development.
Contribution ofrpoB2RNA Polymerase β Subunit Gene to Rifampin Resistance inNocardiaSpecies
Authors: Ishikawa Jun , Chiba Kazuhiro , Kurita Haruyo , Satoh Hiroyuki 
Published: March 2006

ABSTRACTNocardiaspecies are gram-positive environmental saprophytes, but some cause the infectious disease nocardiosis. The complete genomic sequence ofNocardia farcinicaIFM 10152 has been determined, and analyses indicated the presence of two different RNA polymerase β subunit genes,rpoBandrpoB2, in the genome (J. Ishikawa, A. Yamashita, Y. Mikami, Y. Hoshino, H. Kurita, K. Hotta, T. Shiba, and M. Hattori, Proc. Natl. Acad. Sci. USA 101:14925-14930, 2004). These genes share 88.8% identity at the nucleotide level. Moreover, comparison of their amino acid sequences with those of other bacterial RpoB proteins suggested that the nocardial RpoB protein is likely to be rifampin (RIF) sensitive, whereas RpoB2 protein contains substitutions at the RIF-binding region that are likely to confer RIF resistance. Southern analysis indicated thatrpoBduplication is widespread inNocardiaspecies and is correlated with the RIF-resistant phenotype. The introduction ofrpoB2by using a newly developedNocardia-Escherichia colishuttle plasmid vector and transformation system conferred RIF resistance toNocardia asteroidesIFM 0319T, which has neither RIF resistance norrpoBduplication. Furthermore, unmarkedrpoB2deletion mutants ofN. farcinicaIFM 10152 showed no significant resistance to RIF. These results indicated the contribution ofrpoB2to RIF resistance inNocardiaspecies. Since this is the first example of genetic engineering of theNocardiagenome, we believe that this study, as well as our determination of theN. farcinicagenome sequence, will be a landmark inNocardiagenetics.
Interaction of Pleuromutilin Derivatives with the Ribosomal Peptidyl Transferase Center
Authors: Long Katherine S. , Hansen Lykke H. , Jakobsen Lene , Vester Birte 
Published: March 2006

ABSTRACTTiamulin is a pleuromutilin antibiotic that is used in veterinary medicine. The recently published crystal structure of a tiamulin-50S ribosomal subunit complex provides detailed information about how this drug targets the peptidyl transferase center of the ribosome. To promote rational design of pleuromutilin-based drugs, the binding of the antibiotic pleuromutilin and three semisynthetic derivatives with different side chain extensions has been investigated using chemical footprinting. The nucleotides A2058, A2059, G2505, and U2506 are affected in all of the footprints, suggesting that the drugs are similarly anchored in the binding pocket by the common tricyclic mutilin core. However, varying effects are observed at U2584 and U2585, indicating that the side chain extensions adopt distinct conformations within the cavity and thereby affect the rRNA conformation differently. AnEscherichia coliL3 mutant strain is resistant to tiamulin and pleuromutilin, but not valnemulin, implying that valnemulin is better able to withstand an altered rRNA binding surface around the mutilin core. This is likely due to additional interactions made between the valnemulin side chain extension and the rRNA binding site. The data suggest that pleuromutilin drugs with enhanced antimicrobial activity may be obtained by maximizing the number of interactions between the side chain moiety and the peptidyl transferase cavity.
Effect of Farnesol on
Staphylococcus aureus
Biofilm Formation and Antimicrobial Susceptibility
Authors: Jabra-Rizk M. A. , Meiller T. F. , James C. E. , Shirtliff M. E. 
Published: March 2006

ABSTRACT

Staphylococcus aureus
is among the leading pathogens causing bloodstream infections able to form biofilms on host tissue and indwelling medical devices and to persist and cause disease. Infections caused by
S. aureus
are becoming more difficult to treat because of increasing resistance to antibiotics. In a biofilm environment particularly, microbes exhibit enhanced resistance to antimicrobial agents. Recently, farnesol was described as a quorum-sensing molecule with possible antimicrobial properties. In this study, the effect of farnesol on methicillin-resistant and -susceptible strains of
S. aureus
was investigated. With viability assays, biofilm formation assessment, and ethidium bromide uptake testing, farnesol was shown to inhibit biofilm formation and compromise cell membrane integrity. The ability of farnesol to sensitize
S. aureus
to antimicrobials was assessed by agar disk diffusion and broth microdilution methods. For both strains of staphylococci, farnesol was only able to reverse resistance at a high concentration (150 μM). However, it was very successful at enhancing the antimicrobial efficacy of all of the antibiotics to which the strains were somewhat susceptible. Therefore, synergy testing of farnesol and gentamicin was performed with static biofilms exposed to various concentrations of both agents. Plate counts of harvested biofilm cells at 0, 4, and 24 h posttreatment indicated that the combined effect of gentamicin at 2.5 times the MIC and farnesol at 100 μM (22 μg/ml) was able to reduce bacterial populations by more than 2 log units, demonstrating synergy between the two antimicrobial agents. This observed sensitization of resistant strains to antimicrobials and the observed synergistic effect with gentamicin indicate a potential application for farnesol as an adjuvant therapeutic agent for the prevention of biofilm-related infections and promotion of drug resistance reversal.
Binding of Neomycin-Class Aminoglycoside Antibiotics to Mutant Ribosomes with Alterations in the A Site of 16S rRNA
Authors: Hobbie Sven N. , Pfister Peter , Bruell Christian , Sander Peter , François Boris , Westhof Eric , Böttger Erik C. 
Published: March 2006

ABSTRACT

Aminoglycoside antibiotics that bind to the aminoacyl-tRNA site (A site) of the ribosome are composed of a common neamine core in which a glycopyranosyl ring is attached to position 4 of a 2-deoxystreptamine moiety. The core is further substituted by one (ribostamycin), two (neomycin and paromomycin), or three (lividomycin A) additional sugars attached to position 5 of the 2-deoxystreptamine. To study the role of rings III, IV, and V in aminoglycoside binding, we used isogenic
Mycobacterium smegmatis
Δ
rrnB
mutants carrying homogeneous populations of mutant ribosomes with alterations in the 16S rRNA A site. MICs were determined to investigate drug-ribosome interactions, and the results were compared with that of the previously published crystal structure of paromomycin bound to the ribosomal A site. Our analysis demonstrates that the stacking interaction between ring I and G1491 is largely sequence independent, that rings III and IV each increase the strength of drug binding to the ribosome, that ring IV of the 6′-NH
3
+
aminoglycosides compensates for loss of interactions between ring II and U1495 and between ring III and G1491, that the aminoglycosides rely on pseudo-base pairing between ring I and A1408 for binding independently of the number of sugar rings attached to the neamine core, that addition of ring V to the 6′-OH 4,5-aminoglycoside paromomycin does not alter the mode of binding, and that alteration of the U1406 · U1495 wobble base pair to the Watson-Crick interaction pair 1406C-1495G yields ribosomal drug susceptibilities to 4,5-aminoglycosides comparable to those seen with the wild-type A site.
Multidimensional Volumetric Imaging of Pulmonary Infiltrates for Measuring Therapeutic Response to Antifungal Therapy in Experimental Invasive Pulmonary Aspergillosis
Authors: Petraitis Vidmantas , Petraitiene Ruta , Solomon Jeffrey , Kelaher Amy M. , Murray Heidi A. , Mya-San Christine , Bhandary Avi K. , Sein Tin , Avila Nilo A. , Basevicius Algidas , Bacher John , Walsh Thomas J. 
Published: March 2006

ABSTRACT

Pulmonary infiltrates in neutropenic hosts with invasive pulmonary aspergillosis are caused by vascular invasion, hemorrhagic infarction, and tissue necrosis. Monitoring the dynamics of pulmonary infiltrates of invasive aspergillosis is an important tool for assessing response to antifungal therapy. We, therefore, introduced a multidimensional volumetric imaging (MDVI) method for analysis of the response of the volume of pulmonary infiltrates over time to antifungal therapy in experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. We developed a semiautomatic method to measure the volume of lung lesions, which was implemented as an extension of the MEDx visualization and analysis software using ultrafast computerized tomography (UFCT). Volumetric infiltrate measures were compared with UFCT reading, histopathological resolution of lesions, microbiological clearance of
Aspergillus fumigatus
, and galactomannan index (GMI). We also studied the MDVI method for consistency and reproducibility in comparison to UFCT. Treatment groups consisted of deoxycholate amphotericin B (DAMB) at 0.5 or 1 mg/kg of body weight/day and untreated controls (UC). Therapeutic monitoring of pulmonary infiltrates using MDVI demonstrated a significant decrease in the infiltrate volume in DAMB-treated rabbits in comparison to UC (
P
≤ 0.001). Volumetric data by MDVI correlated with conventional CT pulmonary scores (
r
= 0.83,
P
≤ 0.001). These results correlated with validated biological endpoints: pulmonary infarct scores (
r
= 0.85,
P
≤ 0.001), lung weights (
r
= 0.76,
P
≤ 0.01), residual fungal burden (
r
= 0.65,
P
≤ 0.05), and GMI (
r
= 0.78,
P
≤ 0.01). MDVI correlated with key biological markers, improved the objectivity of radiological assessment of therapeutic response to antifungal therapy, and warrants evaluation for monitoring therapeutic response in immunocompromised patients with invasive aspergillosis.
Microflora Changes with Norfloxacin and Pivmecillinam in Women with Recurrent Urinary Tract Infection
Authors: Norinder Birgit Stattin , Norrby Ragnar , Palmgren Ann-Chatrin , Hollenberg Sofia , Eriksson Ulla , Nord Carl Erik 
Published: March 2006

ABSTRACT

Similar changes in the periurethral and vaginal microflora were observed in 19 women with recurrent urinary tract infection following treatment with norfloxacin (NOR) or pivmecillinam (PIV).
Escherichia coli
strains were suppressed by both treatments.
Staphylococcus
spp. and enterococci colony counts increased following PIV treatment in the periurethral flora but remained stable with NOR.
Genetic Basis of Tetracycline and Minocycline Resistance in Potentially Probiotic
Lactobacillus plantarum
Strain CCUG 43738
Authors: Huys Geert , D'Haene Klaas , Swings Jean 
Published: March 2006

ABSTRACT

The potentially probiotic strain
Lactobacillus plantarum
CCUG 43738, which displayed atypical phenotypic resistance to tetracycline (MIC, 512 μg/ml) and minocycline (MIC, 256 μg/ml), was found to contain a
tet
(S) gene located on a plasmid of approximately 14 kb. Plasmid curing with novobiocin eliminated this plasmid and restored the tetracycline-susceptible phenotype of the host strain.
Variability in the Region Downstream of the
bla
CMY-2
β-Lactamase Gene in
Escherichia coli
and
Salmonella enterica
Plasmids
Authors: Kang Min-Su , Besser Thomas E. , Call Douglas R. 
Published: March 2006

ABSTRACT

We used sequencing and PCR mapping to investigate the regions flanking the
bla
CMY-2
β-lactamase gene carried by plasmids from
Escherichia coli
and
Salmonella enterica
. Results revealed genetic heterogeneity in the region downstream from
bla
CMY-2
and identified a putative transposable element bearing
bla
CMY-2
.
Large Conjugative Plasmids from Clinical Strains of
Salmonella enterica
Serovar Virchow Contain a Class 2 Integron in Addition to Class 1 Integrons and Several Non-Integron-Associated Drug Resistance Determinants
Authors: Rodríguez Irene , Rodicio M. Rosario , Mendoza M. Carmen , Cruz Martín M. 
Published: March 2006

ABSTRACT

Two large conjugative resistance (R) plasmids from clinical strains of
Salmonella enterica
serovar Virchow carried a class 2 integron with the 5′ conserved sequence (5′CS)-
dfrA1-sat1-aadA1
-3′CS gene array, which is associated with defective Tn
7
transposons. In addition, each contained a different class 1 integron (with 5′CS-
aadA1
-3′CS or 5′CS-
sat-smr-aadA1
-3′CS gene arrays) linked to Tn
21
-Tn
9
sequences, and several non-integron-associated R determinants. An intact copy of Tn
7
(including the class 2 integron) was present in the chromosome of each strain.