bluuebunny/crossref_metadata_2025_split huggingface dataset:
PreclinicalIn VitroandIn VivoCharacterization of the Fully Human Monoclonal IgM Antibody KBPA101 Specific forPseudomonas aeruginosaSerotype IATS-O11
Authors: Horn Michael P. , Zuercher Adrian W. , Imboden Martin A. , Rudolf Michael P. , Lazar Hedvika , Wu Hong , Hoiby Niels , Fas Stefanie C. , Lang Alois B. 
Published: March 2010

ABSTRACTPseudomonas aeruginosainfection in ventilator-associated pneumonia is a serious and often life-threatening complication in intensive care unit patients, and new treatment options are needed. We used B-cell-enriched peripheral blood lymphocytes from a volunteer immunized with aP. aeruginosaO-polysaccharide-toxin A conjugate vaccine to generate human hybridoma cell lines producing monoclonal antibodies specific for individualP. aeruginosalipopolysaccharide serotypes. The fully human monoclonal antibody secreted by one of these lines, KBPA101, is an IgM/κ antibody that bindsP. aeruginosaof International Antigenic Typing System (IATS) serotype O11 with high avidity (5.81 × 107M−1± 2.8 × 107M−1) without cross-reacting with other serotypes. KBPA101 specifically opsonized theP. aeruginosaof IATS O11 serotype and mediated complement-dependent phagocytosisin vitroby the human monocyte-like cell line HL-60 at a very low concentration (half-maximal phagocytosis at 0.16 ng/ml).In vivoevaluation of KBPA101 demonstrated a dose-response relationship for protection against systemic infections in a murine burn wound sepsis model, where 70 to 100% of animals were protected against lethal challenges withP. aeruginosaat doses as low as 5 μg/animal. Furthermore, a high efficacy of KBPA101 in protection from local respiratory infections in an acute lung infection model in mice was demonstrated. Preclinical toxicology evaluation on human tissue, in rabbits, and in mice did not indicate any toxicity of KBPA101. Based on these preclinical findings, the first human clinical trials have been initiated.
Characterization of DIM-1, an Integron-Encoded Metallo-β-Lactamase from a
Pseudomonas stutzeri
Clinical Isolate in the Netherlands
Authors: Poirel Laurent , Rodríguez-Martínez Jose-Manuel , Al Naiemi Nashwan , Debets-Ossenkopp Yvette J. , Nordmann Patrice 
Published: March 2010

ABSTRACT

A carbapenem-resistant
Pseudomonas stutzeri
strain isolated from a Dutch patient was analyzed in detail. This isolate produced a metallo-β-lactamase (MBL) whose gene, with 43.5% GC content, was cloned and expressed in
Escherichia coli.
β-Lactamase DIM-1 (for
D
utch
im
ipenemase) was weakly related to other Ambler class B β-lactamases, sharing <52% amino acid identity with the most closely related MBL, GIM-1, and 45% identity with IMP-type MBLs. The β-Lactamase DIM-1 significantly hydrolyzed broad-spectrum cephalosporins and carbapenems and spared aztreonam. This MBL gene was embedded in a class 1 integron containing two other gene cassettes, encoding resistance to aminoglycosides and disinfectants, that was located on a 70-kb plasmid.
In Vitro
Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli
Authors: Page Malcolm G. P. , Dantier Clothilde , Desarbre Eric 
Published: March 2010

ABSTRACT

BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR)
Pseudomonas aeruginosa
and
Acinetobacter
sp. isolates, including many carbapenem-resistant strains. The MIC
90
s were 4 μg/ml for MDR
Acinetobacter
spp. and 8 μg/ml for MDR
P. aeruginosa
, whereas the MIC
90
of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both
Acinetobacter
spp. and
P. aeruginosa
, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the
Enterobacteriaceae
family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of
Escherichia
coli
rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.
Population Pharmacokinetics of Micafungin in Neonates and Young Infants
Authors: Hope William W. , Smith P. Brian , Arrieta Antonio , Buell Donald N. , Roy Michael , Kaibara Atsunori , Walsh Thomas J. , Cohen-Wolkowiez Michael , Benjamin Daniel K. 
Published: March 2010

ABSTRACT

Micafungin is an echinocandin with potent activity against
Candida
spp. Hematogenous
Candida
meningoencephalitis (HCME) is a frequent complication of disseminated
Candida
infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).
Impact of Different Carbapenems and Regimens of Administration on Resistance Emergence for Three Isogenic
Pseudomonas aeruginosa
Strains with Differing Mechanisms of Resistance
Authors: Louie Arnold , Bied Adam , Fregeau Christine , Van Scoy Brian , Brown David , Liu Weiguo , Bush Karen , Queenan Anne-Marie , Morrow Brian , Khashab Mohammed , Kahn James B. , Nicholson Susan , Kulawy Robert , Drusano G. L. 
Published: March 2010

ABSTRACT

We compared drugs (imipenem and doripenem), doses (500 mg and 1 g), and infusion times (0.5 and 1.0 [imipenem], 1.0 and 4.0 h [doripenem]) in our hollow-fiber model, examining cell kill and resistance suppression for three isogenic strains of
Pseudomonas aeruginosa
PAO1. The experiments ran for 10 days. Serial samples were taken for total organism and resistant subpopulation counts. Drug concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry (LC/MS/MS). Free time above the MIC (time > MIC) was calculated using ADAPT II. Time to resistance emergence was examined with Cox modeling. Cell kill and resistance emergence differences were explained, in the main, by differences in potency (MIC) between doripenem and imipenem. Prolonged infusion increased free drug time > MIC and improved cell kill. For resistance suppression, the 1-g, 4-h infusion was able to completely suppress resistance for the full period of observation for the wild-type isolate. For the mutants, control was ultimately lost, but in all cases, this was the best regimen. Doripenem gave longer free time > MIC than imipenem and, therefore, better cell kill and resistance suppression. For the wild-type organism, the 1-g, 4-h infusion regimen is preferred. For organisms with resistance mutations, larger doses or addition of a second drug should be studied.
Phenotypic Susceptibility to Bevirimat in Isolates from HIV-1-Infected Patients without Prior Exposure to Bevirimat
Authors: Margot Nicolas A. , Gibbs Craig S. , Miller Michael D. 
Published: March 2010

ABSTRACTBevirimat (BVM) is the first of a new class of anti-HIV drugs with a novel mode of action known as maturation inhibitors. BVM inhibits the last cleavage of the Gag polyprotein by HIV-1 protease, leading to the accumulation of the p25 capsid-small peptide 1 (SP1) intermediate and resulting in noninfectious HIV-1 virions. Early clinical studies of BVM showed that over 50% of the patients treated with BVM did not respond to treatment. We investigated the impact of prior antiretroviral (ARV) treatment and/or natural genetic diversity on BVM susceptibility by conductingin vitrophenotypic analyses of viruses made from patient samples. We generated 31 recombinant viruses containing the entiregagand protease genes from 31 plasma samples from HIV-1-infected patients with (n= 21) or without (n= 10) prior ARV experience. We found that 58% of the patient isolates tested had a >10-fold reduced susceptibility to BVM, regardless of the patient's ARV experience or the level of isolate resistance to protease inhibitors. Analysis of mutants with site-directed mutations confirmed the role of the V370A SP1 polymorphism (SP1-V7A) in resistance to BVM. Furthermore, we demonstrated for the first time that a capsid polymorphism, V362I (CA protein-V230I), is also a major mutation conferring resistance to BVM. In contrast, none of the previously defined resistance-conferring mutations in Gag selectedin vitro(H358Y, L363M, L363F, A364V, A366V, or A366T) were found to occur among the viruses that we analyzed. Our results should be helpful in the design of diagnostics for prediction of the potential benefit of BVM treatment in HIV-1-infected patients.
Activity of Ceftaroline against Recent Emerging Serotypes of
Streptococcus pneumoniae
in the United States
Authors: Jacobs Michael R. , Good Caryn E. , Windau Anne R. , Bajaksouzian Saralee , Biek Donald , Critchley Ian A. , Sader Helio S. , Jones Ronald N. 
Published: March 2010

ABSTRACT

The
in vitro
activity of ceftaroline against 891 pneumococci collected in 2008 from 22 centers in the United States was investigated. Ceftaroline was the most potent agent tested, with the MICs being <0.008 to 0.5 μg/ml and the MIC
90
s being <0.008 to 0.25 μg/ml against 11 prevailing serotypes. The overall rates of susceptibility were as follows: penicillin G, 86.2%; ceftriaxone, 90.7%; cefuroxime, 70.1%; erythromycin, 61.6%; clindamycin, 79.2%; levofloxacin, 99.4%; and vancomycin, 100%. Serotype 19A isolates were the least susceptible. These results support the use of ceftaroline for the treatment of pneumococcal infections, including those caused by pneumococci resistant to other agents.
Interactions ofEncephalitozoon cuniculiPolar Tube Proteins
Authors: Bouzahzah Boumediene , Nagajyothi Fnu , Ghosh Kaya , Takvorian Peter M. , Cali Ann , Tanowitz Herbert B. , Weiss Louis M. 
Published: March 2010

ABSTRACTMicrosporidia are eukaryotic, obligate intracellular organisms defined by small spores that contain a single invasion organelle, the polar tube, which coils around the interior of the spore. When these parasites infect host cells, the polar tube is discharged from the anterior pole of the spore, pierces the cell, and transfers sporoplasm into the cytoplasm of the host. Three polar tube proteins (PTP1, PTP2, and PTP3) have been identified in this structure. The interactions of these proteins in the assembly and function of the polar tube are not known. This study was undertaken to examine the protein interactions of theEncephalitozoon cuniculipolar tube proteins (EcPTPs). Immunofluorescence and immunoelectron microscopy confirmed the colocalization of EcPTP1, EcPTP2, and EcPTP3 to the polar tube. Experiments using cross-linkers indicated that EcPTP1, EcPTP2, and EcPTP3 form a complex in the polar tube, which was confirmed by immunoprecipitation using EcPTP1 antiserum. Yeast two-hybrid analysis revealed that full-length EcPTP1, EcPTP2, and EcPTP3 interact with each otherin vivo. Both the N and C termini of EcPTP1 were involved in these interactions, but the central region of this protein, which contains a repetitive motif, was not. Further studies of polar tube proteins and their structural interactions may help elucidate the formation of the polar tube during the invasion process.
Probiotic Colonization of the Adherent Mucus Layer of HT29MTXE12 Cells Attenuates
Campylobacter jejuni
Virulence Properties
Authors: Alemka Abofu , Clyne Marguerite , Shanahan Fergus , Tompkins Thomas , Corcionivoschi Nicolae , Bourke Billy 
Published: March 2010

ABSTRACT

The HT29MTXE12 (E12) cell line harbors an adherent mucus layer, providing a novel technique to model mucosal infection
in vitro
. In this study, we have characterized the interaction of
Campylobacter jejuni
with the E12 cell line and exploited its unique mucus layer to examine the potential efficacy of probiotic treatment to attenuate
C. jejuni
virulence properties.
C. jejuni
81-176 colonized and reproduced in E12 mucus. Adhesion to and internalization of
C. jejuni
were enhanced in E12 cells harboring mucus compared to parental cells without mucus. Translocation of
C. jejuni
occurred at early time points following infection.
C. jejuni
aligned with tight junctions and colocalized with the tight junction protein occludin, suggesting a paracellular route of translocation. Probiotic strains
Lactobacillus rhamnosus
R0011,
Lactobacillus helveticus
R0052,
Lactobacillus salivarius
AH102,
Bifidobacterium longum
AH1205, a commercial combination of
L. rhamnosus
R0011 and
L. helveticus
R0052 (Lacidofil), and a cocktail consisting of
L. rhamnosus
,
L. helveticus
, and
L. salivarius
(RhHeSa) colonized E12 mucus and bound to underlying cells. Probiotics attenuated
C. jejuni
association with and internalization into E12 cells and translocation to the basolateral medium of transwells. Live bacteria and prolonged precolonization of E12 cells with probiotics were necessary for probiotic action. These results demonstrate the potential for E12 cells as a model of mucosal pathogenesis and provide a rationale for the further investigation of probiotics as prophylaxis against human campylobacteriosis.
Modulation of Allergic Airway Inflammation by the Oral Pathogen
Porphyromonas gingivalis
Authors: Card Jeffrey W. , Carey Michelle A. , Voltz James W. , Bradbury J. Alyce , Ferguson Catherine D. , Cohen Eric A. , Schwartz Samuel , Flake Gordon P. , Morgan Daniel L. , Arbes Samuel J. , Barrow David A. , Barros Silvana P. , Offenbacher Steven , Zeldin Darryl C. 
Published: March 2010

ABSTRACT

Accumulating evidence suggests that bacteria associated with periodontal disease may exert systemic immunomodulatory effects. Although the improvement in oral hygiene practices in recent decades correlates with the increased incidence of asthma in developed nations, it is not known whether diseases of the respiratory system might be influenced by the presence of oral pathogens. The present study sought to determine whether subcutaneous infection with the anaerobic oral pathogen
Porphyromonas gingivalis
exerts a regulatory effect on allergic airway inflammation. BALB/c mice sensitized and subsequently challenged with ovalbumin exhibited airway hyperresponsiveness to methacholine aerosol and increased airway inflammatory cell influx and Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13) content relative to those in nonallergic controls. Airway inflammatory cell and cytokine contents were significantly reduced by establishment of a subcutaneous infection with
P. gingivalis
prior to allergen sensitization, whereas serum levels of ovalbumin-specific IgE and airway responsiveness were not altered. Conversely, subcutaneous infection initiated after allergen sensitization did not alter inflammatory end points but did reduce airway responsiveness in spite of increased serum IgE levels. These data provide the first direct evidence of a regulatory effect of an oral pathogen on allergic airway inflammation and responsiveness. Furthermore, a temporal importance of the establishment of infection relative to allergen sensitization is demonstrated for allergic outcomes.
Zebrafish as a Model Host for
Candida albicans
Infection
Authors: Chao Chun-Cheih , Hsu Po-Chen , Jen Chung-Feng , Chen I-Hui , Wang Chieh-Huei , Chan Hau-Chien , Tsai Pei-Wen , Tung Kai-Che , Wang Chian-Huei , Lan Chung-Yu , Chuang Yung-Jen 
Published: March 2010

ABSTRACT

In this work, the zebrafish model organism was developed to obtain a minivertebrate host system for a
Candida albicans
infection study. We demonstrated that
C. albicans
can colonize and invade zebrafish at multiple anatomical sites and kill the fish in a dose-dependent manner. Inside zebrafish, we monitored the progression of the
C. albicans
yeast-to-hypha transition by tracking morphogenesis, and we monitored the corresponding gene expression of the pathogen and the early host immune response. We performed a zebrafish survival assay with different
C. albicans
strains (SC5314, ATCC 10231, an
hgc1
mutant, and a
cph1
/
efg1
double mutant) to determine each strain's virulence, and the results were similar to findings reported in previous mouse model studies. Finally, using zebrafish embryos, we monitored
C. albicans
infection and visualized the interaction between pathogen and host myelomonocytic cells
in vivo
. Taken together, the results of this work demonstrate that zebrafish can be a useful host model to study
C. albicans
pathogenesis, and they highlight the advantages of using the zebrafish model in future invasive fungal research.
Role of Excessive Inflammatory Response to
Stenotrophomonas maltophilia
Lung Infection in DBA/2 Mice and Implications for Cystic Fibrosis
Authors: Di Bonaventura Giovanni , Pompilio Arianna , Zappacosta Roberta , Petrucci Francesca , Fiscarelli Ersilia , Rossi Cosmo , Piccolomini Raffaele 
Published: March 2010

ABSTRACT

Stenotrophomonas maltophilia
is a pathogen that causes infections mainly in immunocompromised patients. Despite increased
S. maltophilia
isolation from respiratory specimens of patients with cystic fibrosis (CF), the real contribution of the microorganism to CF pathogenesis still needs to be clarified. The aim of the present study was to evaluate the pathogenic role of
S. maltophilia
in CF patients by using a model of acute respiratory infection in DBA/2 mice following a single exposure to aerosolized bacteria. The pulmonary bacterial load was stable until day 3 and then decreased significantly from day 3 through day 14, when the bacterial load became undetectable in all infected mice. Infection disseminated in most mice, although at a very low level. Severe effects (swollen lungs, large atelectasis, pleural adhesion, and hemorrhages) of lung pathology were observed on days 3, 7, and 14. The clearance of
S. maltophilia
observed in DBA/2 mouse lungs was clearly associated with an early and intense bronchial and alveolar inflammatory response, which is mediated primarily by neutrophils. Significantly higher levels of interleukin-1β (IL-1β), IL-6, IL-12, gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), GROα/KC, MCP-1/JE, MCP-5, macrophage inflammatory protein 1α (MIP-1α), MIP-2, and TARC were observed in infected mice on day 1 with respect to controls. Excessive pulmonary infection and inflammation caused systemic effects, manifested by weight loss, and finally caused a high mortality rate. Taken together, our results show that
S. maltophilia
is not just a bystander in CF patients but has the potential to contribute to the inflammatory process that compromises respiratory function.
HIERARCHICAL REPLICATION TECHNIQUES TO ENSURE CHECKPOINT STORAGE RELIABILITY IN GRID ENVIRONMENT
Authors: BOUABACHE FATIHA , HERAULT THOMAS , FEDAK GILLES , CAPPELLO FRANCK 
Published: March 2010

An efficient and reliable fault tolerance protocol plays a key role in High Performance Computing. Rollback recovery is the most common fault tolerance technique used in High Performance Computing and especially in MPI applications. This technique relies on the reliability of the checkpoint storage. Most of the rollback recovery protocols assume that the checkpoint servers machines are reliable. However, in a grid environment any unit can fail at any moment, including components used to connect different administrative domains. Such failures lead to the loss of a whole set of machines, including the more reliable machines used to store the checkpoints in this administrative domain. Thus it is not safe to rely on the high Mean Time Between Failures of specific machines to store the checkpoint images.This paper introduces a new coordinated checkpoint protocol, which tolerates checkpoint server failures and clusters failures, and ensures a checkpoint storage reliability in a grid environment. To provide this reliability the protocol is based on a replication process. We propose new hierarchical replication strategies that exploit the locality of checkpoint images in order to minimize inter-cluster communication.We evaluate the effectiveness of our two hierarchical replication strategies through simulations against several criteria such as topology and scalability.
A Climatology of Inland Winds from Tropical Cyclones for the Eastern United States
Authors: Kruk Michael C. , Gibney Ethan J. , Levinson David H. , Squires Michael 
Published: March 2010

Abstract
Tropical cyclones pose a significant threat to life and property along coastal regions of the United States. As these systems move inland and dissipate, they can also pose a threat to life and property, through heavy rains, high winds, and other severe weather such as tornadoes. While many studies have focused on the impacts from tropical cyclones on coastal counties of the United States, this study goes beyond the coast and examines the impacts caused by tropical cyclones on inland locations. Using geographical information system software, historical track data are used in conjunction with the radial maximum extent of the maximum sustained winds at 34-, 50-, and 64-kt (1 kt ≈ 0.5 m s−1) thresholds for all intensities of tropical cyclones and overlaid on a 30-km equal-area grid that covers the eastern half of the United States. The result is a series of maps with frequency distributions and an estimation of return intervals for inland tropical storm– and hurricane-force winds. Knowing where the climatologically favored areas are for tropical cyclones, combined with a climatological expectation of the inland penetration frequency of these storms, can be of tremendous value to forecasters, emergency managers, and the public.