bluuebunny/crossref_metadata_2025_split huggingface dataset:
SPINOZA AND PROCESS ONTOLOGY
Authors: Di Poppa Francesca 
Published: September 2010

abstractIn this paper, I put forward some remarks supporting a reading of Spinoza's metaphysics in terms of process ontology, that is, the notion that processes or activities, rather than things, are the most basic entities. I suggest that this reading, while not the only possible one, offers advantages over the traditional substance‐properties interpretation. While this claim may sound implausible vis‐à‐vis Spinoza's language of ‘substance’ and ‘attributes’, I show that process ontology illuminates important features of Spinoza's thought and can facilitate solutions to some interpretive problems.
CONSTRUCTIVIST EXPERIMENTAL PHILOSOPHY ON WELL‐BEING AND VIRTUE
Authors: Braddock Matthew 
Published: September 2010

abstractWhat is the nature of human well‐being? This paper joins the ancient debate by rejuvenating an ancient claim that is quite unfashionable among moral philosophers today, namely, the Aristotelian claim that moral virtue is (non‐instrumentally) necessary for human well‐being. Call it the Aristotelian Virtue Condition (AVC). This view can be revived for contemporary debate by a state‐of‐the‐art approach that we might callconstructivist experimental philosophy, which takes as its goal the achievement of a reasonable constructivist account of well‐being and takes the investigation of actual folk intuitions as the central means to achieving that goal. The paper motivates this approach and challenges the commonplace philosophical rejection of AVC by arguing (1) that folk intuitions should count as evidence in the debate, especially if we aim at a constructivist account of well‐being, (2) that folk intuitions can be accurately elicited through a thought experiment (the “Crib Test”), and (3) that there is some reason (subject to experimental confirmation) for thinking that folk intuitions, thus elicited, support AVC. Aristotelian ethics, and indeed the entire virtue ethics tradition, has come under fire recently by empirically informed philosophers who question the empirical adequacy of the postulation of robust character traits, but regardless of how that debate turns out, other parts of this tradition might be empirically supported rather than undermined. This paper sketches a promising, empirically informed way of supporting Aristotelian views of well‐being.
Amikacin Monotherapy for Sepsis Caused by Panresistant
Pseudomonas aeruginosa
Authors: Layeux Brice , Taccone Fabio Silvio , Fagnoul David , Vincent Jean-Louis , Jacobs Frédérique 
Published: September 2010

ABSTRACT

Two patients with severe sepsis due to panresistant
Pseudomonas aeruginosa
, deteriorating despite therapy with colistin and β-lactams, were cured with a high daily dose (25 to 50 mg/kg) of amikacin to obtain a peak/MIC ratio of at least 8 to 10 (MIC = 16 μg/ml). Concomitant use of continuous venovenous hemodiafiltration (CVVHDF) provided no deterioration in renal function after treatment. High dosage of aminoglycosides combined with CVVHDF may represent a valuable therapeutic option for infection due to multiresistant pathogens.
Tolerance of Benznidazole in Treatment of Chagas' Disease in Adults
Authors: Pinazo María-Jesús , Muñoz José , Posada Elizabeth , López-Chejade Paulo , Gállego Montserrat , Ayala Edgar , del Cacho Elena , Soy Dolors , Gascon Joaquim 
Published: September 2010

ABSTRACT

Chagas’ disease is an emerging public health problem in areas where the disease is not endemic. Treatment with benznidazole has shown efficacy in the acute stage of the disease, but its efficacy in the chronic stage remains controversial, and unwanted side effects are more frequent and severe in adults than in children. This study describes the profile of side effects of benznidazole in a cohort of
Trypanosoma cruzi
-infected patients in a European country.
Pharmacokinetics and Pharmacogenomics of Once-Daily Raltegravir and Atazanavir in Healthy Volunteers
Authors: Neely Michael , Decosterd Laurent , Fayet Aurélie , Lee Janice Soo Fern , Margol Ashley , Kanani Meera , di Iulio Julia , von Schoen-Angerer Tido , Jelliffe Roger , Calmy Alexandra 
Published: September 2010

ABSTRACT

Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the
UGT1A1
genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ≥3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods.
UGT1A1
promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir
C
tau
, or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval,
P
value) for plasma raltegravir
C
tau
, area under the concentration-time curve from 0 to 12 h (AUC
0-12
), and raltegravir-glucuronide/raltegravir AUC
0-12
were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a
UGT1A1
reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the
C
tau
with a once-daily raltegravir dose of 400 mg similar to the
C
tau
with the standard twice-daily dose.
UGT1A1
promoter variants did not significantly influence this interaction.
Preclinical Characterization of BI 201335, a C-Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A Protease
Authors: White Peter W. , Llinàs-Brunet Montse , Amad Ma'an , Bethell Richard C. , Bolger Gordon , Cordingley Michael G. , Duan Jianmin , Garneau Michel , Lagacé Lisette , Thibeault Diane , Kukolj George 
Published: September 2010

ABSTRACTBI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b withKivalues of 2.6 and 2.0 nM, respectively.Kivalues of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replicationin vitrowith 50% effective concentrations (EC50s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profilein vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with goodin vitroand animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.
Emergence of Metallo-β-Lactamase NDM-1-Producing Multidrug-Resistant
Escherichia coli
in Australia
Authors: Poirel Laurent , Lagrutta Emilie , Taylor Peter , Pham Jeanette , Nordmann Patrice 
Published: September 2010

ABSTRACT

A multidrug-resistant
Escherichia coli
isolate recovered in Australia produced a carbapenem-hydrolyzing β-lactamase. Molecular investigations revealed the first identification of the
bla
NDM-1
metallo-β-lactamase gene in that country. In addition, this
E. coli
isolate expressed the extended-spectrum β-lactamase CTX-M-15, together with two 16S rRNA methylases, namely, ArmA and RmtB, conferring a high level of resistance to aminoglycosides.
Inadequate Binding of Immune Regulator Factor H Is Associated with Sensitivity ofBorrelia lusitaniaeto Human Complement
Authors: Dieterich Roswitha , Hammerschmidt Claudia , Richter Dania , Skerka Christine , Wallich Reinhard , Matuschka Franz-Rainer , Zipfel Peter F. , Kraiczy Peter 
Published: September 2010

ABSTRACTSpirochetes belonging to theBorrelia burgdorferisensu lato complex differ in resistance to complement-mediated killing by human serum. Here, we characterize complement sensitivity of a panel ofB. lusitaniaeisolates derived from ticks collected in Germany and Portugal as well as one patient-derived isolate, PoHL. All isolates are highly susceptible to complement-mediated lysis in human serum and activate complement predominantly by the alternative pathway, leading to an increased deposition of complement components C3, C6, and the terminal complement complex. Interestingly, serum-sensitiveB. lusitaniaeisolates were able to bind immune regulator factor H (CFH), and some strains also bound CFH-related protein 1 (CFHR1) and CFHR2. Moreover, CFH bound to the surface ofB. lusitaniaewas inefficient in mediating C3b conversion. Furthermore, the identification and characterization of a potential CFH-binding protein, OspE, revealed that this molecule possesses a significantly reduced binding capacity for CFH compared to that of CFH-binding OspE paralogs expressed by various serum-resistantBorreliaspecies. This finding suggests that a reduced binding capability of CFH is associated with an increased serum sensitivity ofB. lusitaniaeto human complement.
Epithelial Cell-Derived S100 Calcium-Binding Proteins as Key Mediators in the Hallmark Acute Neutrophil Response duringCandidaVaginitis
Authors: Yano Junko , Lilly Elizabeth , Barousse Melissa , Fidel Paul L. 
Published: September 2010

ABSTRACTVulvovaginal candidiasis (VVC), caused byCandidaspecies, is a significant problem in women of childbearing age. Similar to clinical observations, a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in a subset of mice without affecting vaginal fungal burden. We hypothesize that the vaginal PMN infiltrate and accompanying inflammation are not protective but instead are responsible for the symptoms of infection. The purpose of this study was to identify the signal(s) associated with the PMN response in the established mouse model. Vaginal lavage fluid from inoculated mice were categorized base on PMN counts, evaluated for PMN chemotactic activity and analyzed by SDS-PAGE and mass spectrometry (MS) for unique protein identification. The lavage fluid from inoculated mice with high, but not low, PMN levels showed increased chemotactic activity. Likewise, SDS-PAGE of lavage fluid with high PMN levels showed distinct protein patterns. MS revealed that bands at 6 and 14 kDa matched the PMN chemotactic calcium-binding proteins (CBPs), S100A8 and S100A9, respectively. The presence of the CBPs in lavage fluid was confirmed by Western blots and enzyme-linked immunosorbent assay. Vaginal tissues and epithelial cells from inoculated mice with high PMN levels stained more intensely and exhibited increased mRNA transcripts for both proteins compared to those in mice with low PMN levels. Subsequent antibody neutralization showed significant abrogation of the chemotactic activity when the lavage fluid was treated with anti-S100A8, but not anti-S100A9, antibodies. These results reveal that the PMN chemotactic CBP S100A8 and S100A9 are produced by vaginal epithelial cells following interaction withCandidaand that S100A8 is a strong candidate responsible for the robust PMN migration during experimental VVC.
Development of Two Animal Models To Study the Function of
Vibrio parahaemolyticus
Type III Secretion Systems
Authors: Piñeyro Pablo , Zhou Xiaohui , Orfe Lisa H. , Friel Patrick J. , Lahmers Kevin , Call Douglas R. 
Published: September 2010

ABSTRACT

Vibrio parahaemolyticus
is an emerging food- and waterborne pathogen that encodes two type III secretion systems (T3SSs). Previous studies have linked type III secretion system 1 (T3SS1) to cytotoxicity and T3SS2 to intestinal fluid accumulation, but animal challenge models needed to study these phenomena are limited. In this study we evaluated the roles of the T3SSs during infection using two novel animal models: a model in which piglets were inoculated orogastrically and a model in which mice were inoculated in their lungs (intrapulmonarily). The bacterial strains employed in this study had equivalent growth rates and beta-hemolytic activity based on
in vitro
assays. Inoculation of 48-h-old conventional piglets with 10
11
CFU of the wild-type strain (NY-4) or T3SS1 deletion mutant strains resulted in acute, self-limiting diarrhea, whereas inoculation with a T3SS2 deletion mutant strain failed to produce any clinical symptoms. Intrapulmonary inoculation of C57BL/6 mice with the wild-type strain and T3SS2 deletion mutant strains (5 × 10
5
CFU) induced mortality or a moribund state within 12 h (80 to 100% mortality), whereas inoculation with a T3SS1 deletion mutant or a T3SS1 T3SS2 double deletion mutant produced no mortality. Bacteria were recovered from multiple organs regardless of the strain used in the mouse model, indicating that the mice were capable of clearing the lung infection in the absence of a functional T3SS1. Because all strains had a similar beta-hemolysin phenotype, we surmise that thermostable direct hemolysin (TDH) plays a limited role in these models. The two models introduced herein produce robust results and provide a means to determine how different T3SS1 and T3SS2 effector proteins contribute to pathogenesis of
V. parahaemolyticus
infection.
Branched-Chain Fatty Acids Promote
Listeria monocytogenes
Intracellular Infection and Virulence
Authors: Sun Yvonne , O'Riordan Mary X. D. 
Published: September 2010

ABSTRACT

Anteiso-branched-chain fatty acids (BCFA) represent the dominant group of membrane fatty acids and have been established as crucial determinants in resistance against environmental stresses in
Listeria monocytogenes
, a facultative intracellular pathogen. Here, we investigate the role of anteiso-BCFA in
L. monocytogenes
virulence by using mutants deficient in branched-chain alpha-keto acid dehydrogenase (BKD), an enzyme complex involved in the synthesis of BCFA. In tissue culture models of infection, anteiso-BCFA contributed to intracellular growth and survival in macrophages and significantly enhanced plaque formation upon prolonged infection in L2 fibroblasts. The intracellular defects observed could be attributed partially to insufficient listeriolysin O (LLO) production, indicating a requirement for anteiso-BCFA in regulating virulence factor production. In a murine model of infection, the BKD-deficient mutant was highly attenuated, further emphasizing the importance of BKD-mediated metabolism in
L. monocytogenes
virulence. This study demonstrates an underappreciated role for BCFA in bacterial pathogenesis, which may provide insight into the development and application of antimicrobial agents.
Enteroaggregative
Escherichia coli
Disrupts Epithelial Cell Tight Junctions
Authors: Strauman Maura C. , Harper Jill M. , Harrington Susan M. , Boll Erik Juncker , Nataro James P. 
Published: September 2010

ABSTRACT

Enteroaggregative
Escherichia coli
(EAEC) is responsible for inflammatory diarrhea in diverse populations, but its mechanisms of pathogenesis have not been fully elucidated. We have used a previously characterized polarized intestinal T84 cell model to investigate the effects of infection with EAEC strain 042 on tight junction integrity. We find that infection with strain 042 induces a decrease in transepithelial electrical resistance (TER) compared to uninfected controls and to cells infected with commensal
E. coli
strain HS. When the infection was limited after 3 h by washing and application of gentamicin, we observed that the TER of EAEC-infected monolayers continued to decline, and they remained low even as long as 48 h after the infection. Cells infected with the afimbrial mutant strain 042
aafA
exhibited TER measurements similar to those seen in uninfected monolayers, implicating the aggregative adherence fimbriae II (AAF/II) as necessary for barrier dysfunction. Infection with wild-type strain 042 induced aberrant localization of the tight junction proteins claudin-1 and, to a lesser degree, occludin. EAEC-infected T84 cells exhibited irregular shapes, and some cells became elongated and/or enlarged; these effects were not observed after infection with commensal
E. coli
strain HS or 042
aafA
. The effects on tight junctions were also observed with AAF/I-producing strain JM221, and an afimbrial mutant was similarly deficient in inducing barrier dysfunction. Our results show that EAEC induces epithelial barrier dysfunction
in vitro
and implicates the AAF adhesins in this phenotype.
Characterization of Toxin Plasmids in
Clostridium perfringens
Type C Isolates
Authors: Gurjar Abhijit , Li Jihong , McClane Bruce A. 
Published: September 2010

ABSTRACT

Clostridium perfringens
type C isolates cause enteritis necroticans in humans or necrotizing enteritis and enterotoxemia in domestic animals. Type C isolates always produce alpha toxin and beta toxin but often produce additional toxins, e.g., beta2 toxin or enterotoxin. Since plasmid carriage of toxin-encoding genes has not been systematically investigated for type C isolates, the current study used Southern blot hybridization of pulsed-field gels to test whether several toxin genes are plasmid borne among a collection of type C isolates. Those analyses revealed that the surveyed type C isolates carry their beta toxin-encoding gene (
cpb
) on plasmids ranging in size from ∼65 to ∼110 kb. When present in these type C isolates, the beta2 toxin gene localized to plasmids distinct from the
cpb
plasmid. However, some enterotoxin-positive type C isolates appeared to carry their enterotoxin-encoding
cpe
gene on a
cpb
plasmid. The
tpeL
gene encoding the large clostridial cytotoxin was localized to the
cpb
plasmids of some
cpe
-negative type C isolates. The
cpb
plasmids in most surveyed isolates were found to carry both IS
1151
sequences and the
tcp
genes, which can mediate conjugative
C. perfringens
plasmid transfer. A
dcm
gene, which is often present near
C. perfringens
plasmid-borne toxin genes, was identified upstream of the
cpb
gene in many type C isolates. Overlapping PCR analyses suggested that the toxin-encoding plasmids of the surveyed type C isolates differ from the
cpe
plasmids of type A isolates. These findings provide new insight into plasmids of proven or potential importance for type C virulence.
In VivoDiscrimination of Type 3 Secretion System-Positive and -NegativePseudomonas aeruginosavia a Caspase-1-Dependent Pathway
Authors: Wangdi Tamding , Mijares Lilia A. , Kazmierczak Barbara I. 
Published: September 2010

ABSTRACTMicrobe-associated molecular patterns are recognized by Toll-like receptors of the innate immune system. This recognition enables a rapid response to potential pathogens but does not clearly provide a way for the innate immune system to discriminate between virulent and avirulent microbes. We find that pulmonary infection of mice with type 3 translocation-competentPseudomonas aeruginosatriggers a rapid inflammatory response, while infection with isogenic translocation-deficient mutants does not. Discrimination between translocon-positive and -negative bacteria requires caspase-1 activity in bone marrow-derived cells and interleukin-1 receptor signaling. Thus, the activation of caspase-1 by bacteria expressing type 3 secretion systems allows for rapid recognition of bacteria expressing conserved functions associated with virulence.
VORONOI DIAGRAM OF POLYGONAL CHAINS UNDER THE DISCRETE FRÉCHET DISTANCE
Authors: BEREG SERGEY , BUCHIN KEVIN , BUCHIN MAIKE , GAVRILOVA MARINA , ZHU BINHAI 
Published: September 2010

Polygonal chains are fundamental objects in many applications like pattern recognition and protein structure alignment. A well-known measure to characterize the similarity of two polygonal chains is the (continuous/discrete) Fréchet distance. In this paper, for the first time, we consider the Voronoi diagram of polygonal chains in d-dimension under the discrete Fréchet distance. Given a set [Formula: see text] of n polygonal chains in d-dimension, each with at most k vertices, we prove fundamental properties of such a Voronoi diagram [Formula: see text]. Our main results are summarized as follows. • The combinatorial complexity of [Formula: see text] is at most O(ndk+∊). • The combinatorial complexity of [Formula: see text] is at least Ω(ndk) for dimension d = 1, 2; and Ω(nd(k-1)+2) for dimension d > 2.
TENDON REFLEX AND STRATEGIES FOR QUANTIFICATION, WITH NOVEL METHODS INCORPORATING WIRELESS ACCELEROMETER REFLEX QUANTIFICATION DEVICES, A PERSPECTIVE REVIEW
Authors: LEMOYNE ROBERT , MASTROIANNI TIMOTHY , COROIAN CRISTIAN , GRUNDFEST WARREN 
Published: September 2010

The deep tendon reflex is a fundamental aspect of a neurological examination. The two major parameters of the tendon reflex are response and latency, which are presently evaluated qualitatively during a neurological examination. The reflex loop is capable of providing insight into the status and therapy response of both upper and lower motor neuron syndromes. Attempts have been made to ascertain reflex response and latency; however, these systems are relatively complex, resource intensive, with issues of consistent and reliable accuracy. The solution presented is a wireless quantified reflex device using tandem three-dimensional (3D) wireless accelerometers to obtain response based on acceleration waveform amplitude and latency derived from temporal acceleration waveform disparity. Three specific aims have been established for the proposed wireless quantified reflex device:(1) Demonstrate the wireless quantified reflex device is reliably capable of ascertaining quantified reflex response and latency using a quantified input.(2) Evaluate the precision of the device using an artificial reflex system.(3) Conduct a longitudinal study respective of subjects with healthy patellar tendon reflexes, using the wireless quantified reflex evaluation device to obtain quantified reflex response and latency.Aim 1 has led to a steady evolution of the wireless quantified reflex device from a singular 2D wireless accelerometer capable of measuring reflex response to a tandem 3D wireless accelerometer capable of reliably measuring reflex response and latency. The hypothesis for aim 1 is that a reflex quantification device can be established for reliably measuring reflex response and latency for the patellar tendon reflex, comprised of an integrated system of wireless 3D MEMS accelerometers. Aim 2 further emphasized the reliability of the wireless quantified reflex device by evaluating an artificial reflex system. The hypothesis for aim 2 is that the wireless quantified reflex device can obtain reliable reflex parameters (response and latency) from an artificial reflex device. Aim 3 synthesizes the findings relevant to aim 1 and 2, while applying the wireless accelerometer reflex quantification device to a longitudinal study of healthy patellar tendon reflexes. The hypothesis for aim 3 is that during a longitudinal evaluation of the deep tendon reflex the parameters for reflex response and latency can be measured with a considerable degree of accuracy, reliability, and reproducibility. Enclosed is a detailed description of a wireless quantified reflex device with research findings and potential utility of the system, inclusive of a comprehensive description of tendon reflexes, prior reflex quantification systems, and correlated applications.