bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penetration of Meropenem into Epithelial Lining Fluid of Patients with Ventilator-Associated Pneumonia
Authors: Lodise T. P. , Sorgel F. , Melnick D. , Mason B. , Kinzig M. , Drusano G. L. 
Published: February 2011

ABSTRACT

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC
ELF
/AUC
plasma
ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC
ELF
/AUC
plasma
ratio. The range of AUC
ELF
/AUC
plasma
penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like
Pseudomonas aeruginosa
, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.
Use of Pharmacokinetic-Pharmacodynamic Analyses To Optimize Therapy with the Systemic Antifungal Micafungin for Invasive Candidiasis or Candidemia
Authors: Andes David , Ambrose Paul G. , Hammel Jeffrey P. , Van Wart Scott A. , Iyer Varsha , Reynolds Daniel K. , Buell Donald N. , Kovanda Laura L. , Bhavnani Sujata M. 
Published: February 2011

ABSTRACT

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC
50
s and MIC
90
s for
Candida
species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (
P
= 0.005). For patients with
Candida parapsilosis
, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (
P
= 0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for
C. parapsilosis
than other
Candida
species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.
Anthelmintics Are Substrates and Activators of Nematode P Glycoprotein
Authors: Kerboeuf Dominique , Guégnard Fabrice 
Published: February 2011

ABSTRACTP glycoproteins (Pgp), members of the ABC transporter superfamily, play a major role in chemoresistance. In nematodes, Pgp are responsible for resistance to anthelmintics, suggesting that they are Pgp substrates, as they are in mammalian cells. However, their binding to nematode Pgp and the functional consequences of this interaction have not been investigated. Our study showed that levamisole and most of the macrocyclic lactones (MLs) are Pgp substrates in nematodes. Ivermectin, although a very good substrate in mammalian cells, is poorly transported. In contrast to their inhibitory effect on mammalian Pgp, these drugs had a stimulatory effect on the transport activity of the reference Pgp substrate rhodamine 123 (R123) in the nematode. This may be due to a specific sequence of nematode Pgp, which shares only 44% identity with mammalian Pgp. Other factors, such as the affinity of anthelmintics for Pgp and their concentration in the Pgp microenvironment, could also differ in nematodes, as suggested by the specific relationship observed between the octanol-water partition coefficient (log P) of MLs and R123 efflux. Nevertheless, some similarities were also observed in the functional activities of the mammalian and nematode Pgp. As in mammalian cells, substrates known to bind the H site (Hoechst 33342 and colchicine) activated the R site, resulting in an increased R123 efflux. Our findings thus show that ML anthelmintics, which inhibit Pgp-mediated efflux in mammals, activate transport activity in nematodes and suggest that several substituents in the ML structure are involved in modulating the stimulatory effect.
Vibrio cholerae Triggers SOS and Mutagenesis in Response to a Wide Range of Antibiotics: a Route towards Multiresistance
Authors: Baharoglu Zeynep , Mazel Didier 
Published: February 2011

ABSTRACT

Antibiotic resistance development has been linked to the bacterial SOS stress response. In
Escherichia coli
, fluoroquinolones are known to induce SOS, whereas other antibiotics, such as aminoglycosides, tetracycline, and chloramphenicol, do not. Here we address whether various antibiotics induce SOS in
Vibrio cholerae
. Reporter green fluorescent protein (GFP) fusions were used to measure the response of SOS-regulated promoters to subinhibitory concentrations of antibiotics. We show that unlike the situation with
E. coli
, all these antibiotics induce SOS in
V. cholerae
.
An Improved Model of the Aspergillus fumigatus CYP51A Protein
Authors: Fraczek M. G. , Bromley M. , Bowyer P. 
Published: February 2011

ABSTRACT

Azole resistance is an increasing clinical problem for
Aspergillus fumigatus
, with the majority of published resistance arising from mutations in the azole target gene CYP51A. Previous structural studies of this protein have suffered from a nonorthologous, low-homology template for homology modeling. Here we present a new model based on the human CYP51A orthologue that provides a higher-quality model for
A. fumigatus
CYP51A.
Putative ATP-Binding Cassette Transporter Is Essential for
Brucella ovis
Pathogenesis in Mice
Authors: Silva Teane M. A. , Paixão Tatiane A. , Costa Érica A. , Xavier Mariana N. , Sá Joicy Cortez , Moustacas Valéria S. , den Hartigh Andreas B. , Carvalho Neta Alcina V. , Oliveira Sérgio C. , Tsolis Renée , Santos Renato L. 
Published: February 2011

ABSTRACT

Brucella ovis
is a major cause of reproductive failure in sheep, which is associated with epididymitis and infertility in rams. Importantly,
B. ovis
is one of the few
Brucella
species that is not zoonotic. Due to the scarcity of studies on
B. ovis
infection, a murine model of infection was developed. The roles of
B. ovis
genes encoding a putative hemagglutinin and an ABC transporter were investigated in the mouse model. The kinetics of
B. ovis
infection were similar in BALB/c and C57BL/6 mice, and both strains of mice developed multifocal microgranulomas in the liver and spleen, but only minimal colonization and histopathological changes were observed in the genital tract. Therefore, the mouse was considered a suitable infection model for
B. ovis
but not for
B. ovis
-induced genital disease. Two mutant strains were generated in this study (the Δ
abcAB
and Δ
hmg
strains). The
B. ovis
Δ
abcAB
strain was attenuated in the spleens and livers of BALB/c mice compared to the wild-type (WT) strain (
P
< 0.001). Conversely, the Δ
hmg
strain infected mice at the same level as WT
B. ovis
, suggesting that a putative hemagglutinin is not required for
B. ovis
pathogenesis. Additionally, the Δ
abcAB
strain did not survive in peritoneal macrophages, extracellularly in the peritoneal cavity, or in RAW 264.7 macrophages. Moreover, infection with the Δ
abcAB
strain was not lethal for male regulatory factor 1-knockout mice, whereas infection with the
B. ovis
WT strain was 100% lethal within 14 days postinfection. These results confirm that the predicted ABC transporter is required for the full virulence and survival of
B. ovis in vivo
.
The Cluster 1 Type VI Secretion System Is a Major Virulence Determinant in
Burkholderia pseudomallei
Authors: Burtnick Mary N. , Brett Paul J. , Harding Sarah V. , Ngugi Sarah A. , Ribot Wilson J. , Chantratita Narisara , Scorpio Angelo , Milne Timothy S. , Dean Rachel E. , Fritz David L. , Peacock Sharon J. , Prior Joanne L. , Atkins Timothy P. , DeShazer David 
Published: February 2011

ABSTRACT

The
Burkholderia pseudomallei
K96243
genome encodes six type VI secretion systems (T6SSs), but little is known about the role of these systems in the biology of
B. pseudomallei
. In this study, we purified recombinant Hcp proteins from each T6SS and tested them as vaccine candidates in the BALB/c mouse model of melioidosis. Recombinant Hcp2 protected 80% of mice against a lethal challenge with
K96243
, while recombinant Hcp1, Hcp3, and Hcp6 protected 50% of mice against challenge. Hcp6 was the only Hcp constitutively produced by
B. pseudomallei in vitro
; however, it was not exported to the extracellular milieu. Hcp1, on the other hand, was produced and exported
in vitro
when the VirAG two-component regulatory system was overexpressed in
trans
. We also constructed six
hcp
deletion mutants (
Δhcp1
through
Δhcp6
) and tested them for virulence in the Syrian hamster model of infection. The 50% lethal doses (LD
50
s) for the
Δhcp2
through
Δhcp6
mutants were indistinguishable from
K96243
(<10 bacteria), but the LD
50
for the
Δhcp1
mutant was >10
3
bacteria. The
hcp1
deletion mutant also exhibited a growth defect in RAW 264.7 macrophages and was unable to form multinucleated giant cells in this cell line. Unlike
K96243
, the
Δhcp1
mutant was only weakly cytotoxic to RAW 264.7 macrophages 18 h after infection. The results suggest that the cluster 1 T6SS is essential for virulence and plays an important role in the intracellular lifestyle of
B. pseudomallei
.
Extensive Polymorphism and Evidence of Immune Selection in a Highly Dominant Antigen Recognized by Bovine CD8 T Cells Specific for Theileria annulata
Authors: MacHugh Niall D. , Weir William , Burrells Alison , Lizundia Regina , Graham Simon P. , Taracha Evans L. , Shiels Brian R. , Langsley Gordon , Morrison W. Ivan 
Published: February 2011

ABSTRACTAlthough parasite strain-restricted CD8 T cell responses have been described for several protozoa, the precise role of antigenic variability in immunity is poorly understood. The tick-borne protozoan parasiteTheileria annulatainfects leukocytes and causes an acute, often fatal lymphoproliferative disease in cattle. Building on previous evidence of strain-restricted CD8 T cell responses toT. annulata, this study set out to identify and characterize the variability of the target antigens. Three antigens were identified by screening expressed parasite cDNAs with specific CD8 T cell lines. In cattle expressing the A10 class I major histocompatibility complex haplotype, A10-restricted CD8 T cell responses were shown to be focused entirely on a single dominant epitope in one of these antigens (Ta9). Sequencing of the Ta9 gene from field isolates ofT. annulatademonstrated extensive sequence divergence, resulting in amino acid polymorphism within the A10-restricted epitope and a second A14-restricted epitope. Statistical analysis of the allelic sequences revealed evidence of positive selection for amino acid substitutions within the region encoding the CD8 T cell epitopes. Sequence differences in the A10-restricted epitope were shown to result in differential recognition by individual CD8 T cell clones, while clones also differed in their ability to recognize different alleles. Moreover, the representation of these clonal specificities within the responding CD8 T cell populations differed between animals. As well as providing an explanation for incomplete protection observed after heterologous parasite challenge of vaccinated cattle, these results have important implications for the choice of antigens for the development of novel subunit vaccines.
Attitudes towards exercise in patients with chronic disease: the influence of comorbid factors on motivation and ability to exercise
Authors: Murphy Claire-Louise , Sheane Barry J , Cunnane Gaye 
Published: February 2011

ABSTRACT

Background
Exercise is an integral part of a healthy lifestyle. It has a well defined role in maintaining health in chronic illness. This study was undertaken to determine attitudes towards exercise in patients admitted to hospital with medical illnesses.

Methods
A questionnaire on attitudes to and extent of exercise was devised and administered to patients admitted to an acute medical unit of a large university teaching hospital in 2008. Data were analysed using SPSS.

Results
107 patients participated, mean age 57 years (range 20–92): 79% had at least one chronic disease, 60% were overweight, 42% did little or no exercise, while 81% did not achieve moderate physical activity. Factors associated with reduced activity included increasing age, alcohol excess, lower education level, and unemployment. Approximately 50% of the patients blamed health problems while the other half cited lack of time or motivation as reasons for not exercising. Only 3% were aware of national or international exercise recommendations.

Conclusions
Much greater awareness of the importance of exercise and its impact on health and longevity is needed. Healthcare providers have an important role in exercise education in patients with acute and chronic disease.
A review on arsenic concentrations in Canadian drinking water
Authors: McGuigan Claire F. , Hamula Camille L.A. , Huang Sarah , Gabos Stephan , Le X. Chris 
Published: February 2011

Recent events have increased public awareness of drinking water quality in Canada. The goal of this review was to examine how much information about arsenic (As) in Canadian drinking water is available. Provincial, territorial, and federal Web sites were searched for information about As in drinking water. Major scientific databases (PubMed, Web of Science) were searched for drinking water As information for all provinces and territories. Resulting information was examined for availability, accessibility, quality, and timeliness. Most provinces provided at least basic fact sheets about As, and several provinces provided comprehensive databases containing actual test results. The vast majority of Canadian municipal drinking water systems with As data show a concentration below 10 μg/L, the current guideline level. Several locations in Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Québec, and Saskatchewan have localized elevations of As (“hotspots”, >10 μg/L As); this information is available at the provincial level, but may not include exact locations nor the degree by which they exceed the current guideline limit of 10 μg/L. For other locations, however, little information is available. The lack of a centralized information source represents a significant obstacle to obtaining drinking water quality data. Although difficult to implement, a centralized and standardized source of national drinking water quality data is urgently needed to determine the effects of As and other contaminants on Canadians.
Differential schemes
Authors: Bardavid Colas 
Published: February 2011

This thesis focuses on the theory --- still under construction --- of differential schemes. The aim of our work is to provide two new perspectives to this theory.
The first perspective is geometric and consists in considering schemes endowed with vector fields instead of differential rings. In this context, we define what is a leaf and what is the trajectory of a point. With the help of these tools, we reinvest and generalize some results of differential Galois theory. Similarly, we show that the Carrà Ferro sheaf is the natural sheaf of the space of leaves of a scheme with vector field. It is also this approach that lead us to prove that, in the reduced case, the Kovacic and Keigher sheaves are isomorphic and that they have the same constant as the Carrà Ferro sheaf.
The second perspective is functorial, and is based on the notion of scheme due to Toën and Vaquié [6]. We prove that the category of differential schemes in the sense similar to the one of these authors is equivalent to the category of schemes endowed with a vector field.
simpcomp
Authors: Effenberger Felix , Spreer Jonathan 
Published: February 2011

simpcomp [4] is an extension (a so called package) to GAP [6], the well known system for computational discrete algebra. The package enables the user to compute numerous properties of (abstract) simplicial complexes, provides functions to construct new complexes from existing ones and an extensive library of triangulations of manifolds. For an introduction to the field of piecewise linear (PL) topology see the books [16] and [11].
The authors acknowledge support by the DFG: simpcomp has partly been developed within the DFG projects Ku 1203/5-2 and Ku 1203/5-3.
Phase I Clinical Study of Seneca Valley Virus (SVV-001),a Replication-Competent Picornavirus, in Advanced Solid Tumors with Neuroendocrine Features
Authors: Rudin Charles M. , Poirier John T. , Senzer Neil N. , Stephenson Joseph , Loesch David , Burroughs Kevin D. , Reddy P. Seshidhar , Hann Christine L. , Hallenbeck Paul L. 
Published: February 2011

Abstract
Purpose: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer.
Experimental Design: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 107 to 1011 vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed.
Results: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 107 vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be &gt;103-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment.
Conclusions: Intravenous SVV-001 administration in patients is well tolerated at doses up to 1011 vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated. Clin Cancer Res; 17(4); 888–95. ©2011 AACR.
Functional Roles ofSrcandFgrin Ovarian Carcinoma
Authors: Kim Hye-Sun , Han Hee Dong , Armaiz-Pena Guillermo N. , Stone Rebecca L. , Nam Eun Ji , Lee Jeong-Won , Shahzad Mian M. K. , Nick Alpa M. , Lee Sun Joo , Roh Ju-Won , Nishimura Masato , Mangala Lingegowda S. , Bottsford-Miller Justin , Gallick Gary E. , Lopez-Berestein Gabriel , Sood Anil K. 
Published: February 2011

AbstractPurpose: Src is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of Src silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of Src activity.Experimental Design: Cell viability after either Src or Fgr silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after Src silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of in vivo Src and/or Fgr silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues.Results: Src silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, Src silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, P = 0.017; 84.3% reduction in HeyA8, P &lt; 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of Src silencing on other SFK members in ovarian cancer cell lines. Src silencing resulted in significantly increased Fgr levels. Dual Src and Fgr silencing in vitro resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of Src and Fgr in vivo using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either Src or Fgr alone in the HeyA8 model (68.8%, P &lt; 0.05).Conclusions: This study demonstrates that, in addition to Src, Fgr plays a biologically significant role in ovarian cancer growth and might represent an important target. Clin Cancer Res; 17(7); 1713–21. ©2011 AACR.