bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Impaired Renal Function on the Pharmacokinetics of Tomopenem (RO4908463/CS-023), a Novel Carbapenem
Authors: Mallalieu Navita L. , Lennon Siân , Liu Mei , Kirkpatrick Christopher , Robson Richard , Luedin Eric , Davies Brian E. 
Published: April 2008

ABSTRACT

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of ≥80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (± standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 ± 35.2 to 1,037 ± 238 μg·h/ml. The maximum concentration of drug in plasma (
C
max
) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in
C
max
of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (
R
2
= 0.97;
P
< 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 ± 0.89 to 0.59 ± 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite.
In Vitro Activity of Telavancin against Resistant Gram-Positive Bacteria
Authors: Krause Kevin M. , Renelli Marika , Difuntorum Stacey , Wu Terry X. , Debabov Dmitri V. , Benton Bret M. 
Published: April 2008

ABSTRACT

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC
90
, 0.5 to 1 μg/ml), streptococci (all MICs, ≤0.12 μg/ml), and VanB-type enterococci (all MICs, ≤2 μg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.
Comparative Surveillance Study of Telavancin Activity against Recently Collected Gram-Positive Clinical Isolates from across the United States
Authors: Draghi Deborah C. , Benton Bret M. , Krause Kevin M. , Thornsberry Clyde , Pillar Chris , Sahm Daniel F. 
Published: April 2008

ABSTRACT

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against
Staphylococcus aureus
and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 μg/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC
90
s, 0.03 to 0.12 μg/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC
90
, 1 μg/ml) and was active against VanB strains of vancomycin-resistant enterococci (MIC
90
, 2 μg/ml) but less active against VanA strains (MIC
90
, 8 to 16 μg/ml). Telavancin also demonstrated activity against vancomycin-intermediate
S. aureus
and vancomycin-resistant
S. aureus
strains (MICs, 0.5 μg/ml to 1.0 μg/ml and 1.0 μg/ml to 4.0 μg/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.
In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in
Staphylococcus aureus
Authors: Robertson Gregory T. , Bonventre Eric J. , Doyle Timothy B. , Du Qun , Duncan Leonard , Morris Timothy W. , Roche Eric D. , Yan Dalai , Lynch A. Simon 
Published: April 2008

ABSTRACT

Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with
Staphylococcus aureus
of CBR-2092, a novel hybrid that combines the rifamycin SV and 4
H
-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent
S. aureus
infections.
Hemolysin of Uropathogenic
Escherichia coli
Evokes Extensive Shedding of the Uroepithelium and Hemorrhage in Bladder Tissue within the First 24 Hours after Intraurethral Inoculation of Mice
Authors: Smith Yarery C. , Rasmussen Susan B. , Grande Kerian K. , Conran Richard M. , O'Brien Alison D. 
Published: April 2008

ABSTRACT

Many uropathogenic
Escherichia coli
(UPEC) strains produce both hemolysin (Hly) and cytotoxic necrotizing factor type 1 (CNF1), and the loci for these toxins are often linked. The conclusion that Hly and CNF1 contribute to urovirulence is supported by the results of epidemiological studies associating the severity of urinary tract infections (UTIs) with toxin production by UPEC isolates. Additionally, we previously reported that mouse bladders and rat prostates infected with UPEC strain CP9 exhibit a more profound inflammatory response than the organs from animals challenged with CP9
cnf
1
and that CNF1 decreases the antimicrobial activities of polymorphonuclear leukocytes. More recently, we created an Hly mutant, CP9Δ
hlyA
1
::
cat
, and showed that it was less hemolytic and destructive for cultured bladder cells than CP9 was. Here we evaluated the relative effects of mutations in
hlyA
1
or
cnf
1
alone or together on the pathogenicity of CP9 in a mouse model of ascending UTI. To do this, we constructed an
hlyA
1
-complemented clone of CP9Δ
hlyA
1
::
cat
and an
hlyA
1
cnf
1
CP9 double mutant. We found that Hly had no influence on bacterial colonization of the bladder or kidneys in single or mixed infections with the wild type and CP9Δ
hlyA
1
::
cat
but that it did provoke sloughing of the uroepithelium and bladder hemorrhage within the first 24 h after challenge. Finally, we confirmed that CNF1 expression induces bladder inflammation and, in particular, as shown in this study, submucosal edema. From these data, we speculate that Hly and CNF1 may be largely responsible for the signs and symptoms of cystitis in humans infected with toxigenic UPEC.
Cholesterol Depletion ReducesHelicobacter pyloriCagA Translocation and CagA-Induced Responses in AGS Cells
Authors: Lai Chih-Ho , Chang Yun-Chieh , Du Shin-Yi , Wang Hung-Jung , Kuo Chun-Hsien , Fang Shih-Hua , Fu Hua-Wen , Lin Hui-Hao , Chiang Ann-Shyn , Wang Wen-Ching 
Published: April 2008

ABSTRACTInfection withHelicobacter pylori cagA-positive strains is associated with gastritis, ulcerations, and gastric cancer. CagA is translocated into infected epithelial cells by a type IV secretion system and can be tyrosine phosphorylated, inducing signal transduction and motogenic responses in epithelial cells. Cellular cholesterol, a vital component of the membrane, contributes to membrane dynamics and functions and is important in VacA intoxication and phagocyte evasion duringH. pyloriinfection. In this investigation, we showed that cholesterol extraction by methyl-β-cyclodextrin reduced the level of CagA translocation and phosphorylation. Confocal microscope visualization revealed that a significant portion of translocated CagA was colocalized with the raft marker GM1 and c-Src during infection. Moreover, GM1 was rapidly recruited into sites of bacterial attachment by live-cell imaging analysis. CagA and VacA were cofractionated with detergent-resistant membranes (DRMs), suggesting that the distribution of CagA and VacA is associated with rafts in infected cells. Upon cholesterol depletion, the distribution shifted to non-DRMs. Accordingly, the CagA-induced hummingbird phenotype and interleukin-8 induction were blocked by cholesterol depletion. Raft-disrupting agents did not influence bacterial adherence but did significantly reduce internalization activity in AGS cells. Together, these results suggest that delivery of CagA into epithelial cells by the bacterial type IV secretion system is mediated in a cholesterol-dependent manner.
The Phenolic Glycolipid ofMycobacterium tuberculosisDifferentially Modulates the Early Host Cytokine Response but Does Not in Itself Confer Hypervirulence
Authors: Sinsimer Daniel , Huet Gaelle , Manca Claudia , Tsenova Liana , Koo Mi-Sun , Kurepina Natalia , Kana Bavesh , Mathema Barun , Marras Salvatore A. E. , Kreiswirth Barry N. , Guilhot Christophe , Kaplan Gilla 
Published: April 2008

ABSTRACTMycobacterium tuberculosispossesses a diversity of potential virulence factors including complex branched lipids such as the phenolic glycolipid PGL-tb. PGL-tb expression by the clinicalM. tuberculosisisolate HN878 has been associated with a less efficient Th1 response and increased virulence in mice and rabbits. It has been suggested that the W-Beijing family is the only group ofM. tuberculosisstrains with an intactpks1-15gene, required for the synthesis of PGL-tb and capable of producing PGL-tb. We have found that some strains with an intactpks1-15do not produce PGL-tb while others may produce a variant of PGL-tb. We examined the early host cytokine response to infection with these strains in vitro to better understand the effect of PGL-tb synthesis on immune responses. In addition, we generated a PGL-tb-producing H37Rv in order to determine the effect of PGL-tb production on the host immune response during infection by a strain normally devoid of PGL-tb synthesis. We observed that PGL-tb production by clinicalM. tuberculosisisolates affected cytokine production differently depending on the background of the strain. Importantly, while ectopic PGL-tb production by H37Rv suppressed the induction of several pro- and anti-inflammatory cytokines in vitro in human monocytes, it did not lead to increased virulence in infected mice and rabbits. Collectively, our data indicate that, while PGL-tb may play a role in the immunogenicity and/or virulence ofM. tuberculosis, it probably acts in concert with other bacterial factors which seem to be dependent on the background of the strain.
Helicobacter pylori
VacA Subdomain Required for Intracellular Toxin Activity and Assembly of Functional Oligomeric Complexes
Authors: Ivie Susan E. , McClain Mark S. , Torres Victor J. , Algood Holly M. Scott , Lacy D. Borden , Yang Rong , Blanke Steven R. , Cover Timothy L. 
Published: April 2008

ABSTRACT

Helicobacter pylori
VacA is a secreted pore-forming toxin that is comprised of two domains, designated p33 and p55. The p55 domain has an important role in the binding of VacA to eukaryotic cell surfaces. A total of 111 residues at the amino terminus of p55 (residues 312 to 422) are essential for the intracellular activity of VacA, which suggests that this region may constitute a subdomain with an activity distinct from cell binding. To investigate the properties of this subdomain, a small deletion mutation (targeting aspartic acid 346 and glycine 347) was introduced into the
H. pylori
chromosomal
vacA
gene. Similar to wild-type VacA, the VacA Δ346-347 mutant protein was proteolytically processed, secreted, and bound to eukaryotic cells. However, VacA Δ346-347 did not cause cell vacuolation or membrane depolarization, and it was impaired in the ability to assemble into large water-soluble oligomeric structures. Interestingly, VacA Δ346-347 was able to physically interact with wild-type VacA to form mixed oligomeric complexes, and VacA Δ346-347 inhibited wild-type vacuolating activity in a dominant-negative manner. These data indicate that the assembly of functional oligomeric VacA complexes is dependent on specific sequences, including amino acids 346 and 347, within the p55 amino-terminal subdomain.
Seismic assessment of rainscreen stucco systems
Authors: Kharrazi Mehdi H.K. , Taylor Graham W. , Ventura Carlos E. 
Published: April 2008

This paper evaluates the comparative and absolute in-plane seismic performance of rainscreen and nonrainscreen stucco exterior cladding systems for residential wood frame construction in British Columbia. In this study, an experimental program including quasi-static and dynamic tests was implemented, comprised of 18 (in-plane) quasi-static tests and two dynamic tests. The principal parameters investigated in this study were type of strapping, type and length of strapping fastener, and type and length of lath fastener. All rainscreen specimens were constructed with a 20 mm air space. The overall conclusion is that both rainscreen and nonrainscreen stucco comply with the code requirements addressing the permissible drifts. Therefore, both stucco systems were found to improve the structural behaviour when used as the lateral resisting system of residential wood frame buildings. This paper concludes with recommendations for seismic refinements to current construction practices.
Determination of optimal microwave curing cycle for fly ash mortars
Authors: Topçu İlker Bekir , Toprak Mehmet Uğur , Akdağ Devrim 
Published: April 2008

Microwave energy can accelerate the hydration of cement, which results in the rapid strength development of concrete. In this paper, prediction of later age compressive strength of fly ash cement mortars, based on the accelerated strength of mortars cured with microwave energy, was investigated. To accelerate curing properly, optimal processing parameters of microwave curing (MC) on Portland cement mortars (CM) and fly ash cement mortars (FA) were first determined and then were applied to mortars. The possible early ages for the strength prediction were found to be at 6 and 8 h for CM and FA, respectively. The error percentages for prediction of CM were ±2.22% and 2.91% for 7 and 28 d, respectively. Error percentages for FA, on the other hand, were ±4.36% and 5.20% for 7 and 28 d, respectively.
Implications of researcher assumptions about perceived relative advantage and compatibility
Authors: Van Slyke Craig , Johnson Richard D. , Hightower Ross , Elgarah Wafa 
Published: April 2008

Although scale reuse is an important and efficient research practice, it may not always be the most appropriate practice. Mechanistically reusing scales developed for a particular context may lead to a variety of undesirable effects. One of the risks is that frequently reused scales can inadvertently begin to alter the definitions of related constructs. When this occurs, a full understanding of the constructs can be lost. Innovation diffusion is one area in which evidence suggests that this has occurred, specifically for relative advantage and compatibility.This article seeks to better understand the risks of mechanistic scale reuse within the information systems field, with a specific focus on the relative advantage and compatibility constructs. We review the information systems literature focusing on IT adoption and diffusion, examining the theoretical and empirical relationships between relative advantage and compatibility. Evidence from this review indicates that there may be both conceptual and empirical overlap between the two, which has led to inconsistent empirical and theoretical treatment of the constructs across studies. We also report an empirical examination of the domain coverage of the scales, which provides evidence that the scales a) exhibit a high degree of conceptual and empirical overlap and b) only represent a subset of their full conceptualization. We offer recommendations for researchers who wish to use these constructs in future work.
Gadamerian Hermeneutics and Irony: Between Strauss and Derrida
Authors: Dostal Robert 
Published: April 2008

AbstractAgainst the background of Gadamer's hermeneutics of trust, for which the primary concern of the hermeneutical enterprise is the matter under discussion, the Sache, this essay raises the question of Gadamer's treatment of irony. Gadamer and Gadamerians have criticized the hermeneutics of suspicion—a hermeneutics that always looks under the surface of what is said to see what is hidden. This would seem to make irony a problematic aspect of texts and discourse for a Gadamerian hermeneutics. Nowhere in Gadamer's corpus can we find an extensive discussion of irony, but Gadamer does raise the question of irony in a provocative way in several important junctures. This essay contrasts Gadamer's treatment of irony to that of Leo Strauss and Jacques Derrida. It explores why for Gadamer irony does not call for a hermeneutics of suspicion.
Derrida and the Ethics of the Im-possible
Authors: Raffoul François 
Published: April 2008

AbstractDerrida often insists that ethics must be the experience and encounter of a certain impossible. A proposition all the more troubling, as it is proposed by Derrida in the context of a return precisely to the conditions of possibility of ethics. It will appear that returning to the possibilities of ethics implies a return to its limits, to its aporias, which are both constitutive and incapacitating, possibilizing and impossibilizing. The purpose of this paper is to begin exploring this aporetic structure of ethics and to identify how it is tied to the impossible. I will pursue this inquiry by reconstituting how Derrida appropriates Heidegger's expression of "possibility of the impossible," and by reconstituting the aporias of the law, of moral decision, of responsibility, and of an ethics of hospitality as welcome of the event of otherness.
Poverty and Public Theology: Advocacy of the Church in Pluralistic Society
Authors: Bedford-Strohm Heinrich 
Published: April 2008

AbstractThis article describes four models of connecting the biblical option for the poor with theological ethics. The charity model denies any political significance of this option. The fundamental critical model connects this theological option exclusively with a confessional critique of western capitalism and its market approach. The political advice model does not give an explicit account of its theological groundings but tries to present practicable political solutions. Finally the public theology model which is advocated in this article connects a clear theological profile with the involvement in the public debate on economic strategies which reflect the option for the poor. For this, public theology has to be bilingual, speaking a theological and a secular language; moreover, because of its involvement in the public debate public theology can be understood as a liberation theology for a democratic society. The article presents Martin Luther and Dietrich Bonhoeffer as public theologians who, in their time, have been advocates for the poor. The memorandum of the German Protestant churches of 2006 on poverty is presented as an example of public theological involvement of the church in our time. The article ends with a reflection on eschatological justice.
Responding to Dr Plant
Authors: Purcell Michael 
Published: April 2008

AbstractThis response to Dr Plant engages with important issues regarding the possibility of using the work of Emmanuel Levinas as a theological tool and resource. Levinas 'and' theology is both an important conjunction and disjunction. The distinction between a theology that is fundamental and a theology that is dogmatic needs to be stressed. Levinas' ethical metaphysics, and his recognition of the need for a theological recuperation of the ethics he espouses, opens up a possible and fundamental theological dialogue which recognizes the fundamental and salvific importance of the ordinary and the everyday in human existence.
The West African Monsoon Dynamics. Part III: The Quasi-Biweekly Zonal Dipole
Authors: Mounier Flore , Janicot Serge , Kiladis George N. 
Published: April 2008

Abstract
This paper presents an investigation of the mechanisms giving rise to the main intraseasonal mode of convection in the African monsoon during northern summer, here identified as the quasi-biweekly zonal dipole (QBZD). The QBZD is primarily characterized by a quasi-stationary zonal dipole of convection whose dimension is larger than the West African monsoon domain, with its two poles centered along the Guinean coast and between 30° and 60°W in the equatorial Atlantic. The QBZD dynamical processes within the Atlantic–Africa domain are examined in some detail. The QBZD has a dipole pattern associated with a Walker-type circulation in the near-equatorial zonal plane. It is controlled both by equatorial atmospheric dynamics through a Kelvin wave–like disturbance propagating eastward between its two poles and by land surface processes over Africa, inducing combined fluctuations in surface temperatures, surface pressure, and low-level zonal winds off the coast of West Africa. When convection is at a minimum over central and West Africa, a lack of cloud cover results in higher net shortwave flux at the surface, which increases surface temperatures and lowers surface pressures. This creates an east–west pressure gradient at the latitude of both the ITCZ (10°N) and the Saharan heat low (20°N), leading to an increase in eastward moisture advection inland. The arrival from the Atlantic of the positive pressure signal associated with a Kelvin wave pattern amplifies the low-level westerly wind component and the moisture advection inland, leading to an increase in convective activity over central and West Africa. Then the opposite phase of the dipole develops. Propagation of the QBZD convective envelope and of the associated 200 high-level velocity potential anomalies is detected from the eastern Pacific to the Indian Ocean. When the effect of the Kelvin wave propagation is removed by filtering, the stationary character of the QBZD is highlighted. The impact of the QBZD in combination with a Kelvin wave is illustrated by a case study of the monsoon onset in 1984.