bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examination of Potential Mechanisms To Explain the Association between Proton Pump Inhibitors and
Clostridium difficile
Infection
Authors: Nerandzic Michelle M. , Pultz Michael J. , Donskey Curtis J. 
Published: August 2009

ABSTRACT

Proton pump inhibitors (PPIs) have been associated with
Clostridium difficile
infection (CDI) in several recent studies. However, other studies have not shown this association, and the mechanism by which PPIs might promote CDI has not been elucidated. We hypothesized two possible mechanisms of causation: first, by raising pH, PPIs may prevent gastric contents from killing
C. difficile
spores; second, gastric contents of PPI-treated patients may promote germination and outgrowth of
C. difficile
spores. Survival rates of spores from six different strains of
C. difficile
in acidic gastric contents were assessed using quantitative cultures on selective media. Germination and outgrowth of spores were assessed by heat shock at 80°C, phase-contrast microscopy, and ethanol shock after incubation for 24 h in the gastric contents of patients and in the gastric, small intestinal, and cecal contents of mice.
C. difficile
spores survived and remained dormant in nonbilious gastric contents with acidic pH. Germination did not occur in unmodified gastric contents of patients but did occur with the addition of taurocholic acid and amino acids. In mice, germination did not occur in gastric contents but did occur in small intestinal and cecal contents. In summary,
C. difficile
spores survived in acidic gastric contents and did not undergo germination and outgrowth in gastric contents, probably due to lack of essential germinants, such as taurocholic acid. Our results suggest that the effects of PPIs in the stomach do not contribute to the pathogenesis of CDI.
Effect of Mild and Moderate Liver Disease on the Pharmacokinetics of Isavuconazole after Intravenous and Oral Administration of a Single Dose of the Prodrug BAL8557
Authors: Schmitt-Hoffmann A. , Roos B. , Spickermann J. , Heep M. , Peterfaí É. , Edwards D. J. , Stoeckel K. 
Published: August 2009

ABSTRACT

Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [
P
< 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease.
Antibiotic Usage and Risk of Colonization and Infection with Antibiotic-Resistant Bacteria: a Hospital Population-Based Study
Authors: Tacconelli Evelina , De Angelis Giulia , Cataldo Maria Adriana , Mantengoli Elisabetta , Spanu Teresa , Pan Angelo , Corti Giampaolo , Radice Anna , Stolzuoli Lucia , Antinori Spinello , Paradisi Franco , Carosi Giampiero , Bernabei Roberto , Antonelli Massimo , Fadda Giovanni , Rossolini Gian Maria , Cauda Roberto 
Published: August 2009

ABSTRACT

Accurate assessment of risk factors for nosocomial acquisition of colonization by antibiotic-resistant bacteria (ARB) is often confounded by scarce data on antibiotic use. A 12-month, nested, multicenter cohort study was conducted. Target ARB were methicillin (meticillin)-resistant
Staphylococcus aureus
(MRSA), vancomycin-resistant enterococci (VRE), and ciprofloxacin-resistant
Pseudomonas aeruginosa
(CR-PA). Nares and rectal swabs were obtained before and after starting antibiotics. Pulsed-field gel electrophoresis was done to define genetic relatedness of the strains. Primary outcomes were (i) the mean time, in days, for acquisition of target ARB colonization in patients previously not colonized; (ii) the rate of acquisition per 1,000 antibiotic-days according to different classes of antibiotics; (iii) the rate of infection caused by the same bacteria as those previously isolated in screening samples; and (iv) the risk factors for ARB acquisition. In total, 6,245 swabs from 864 inpatients were processed. The rate of acquisition was 3%, 2%, and 1% for MRSA, VRE, and CR-PA, respectively. The rate of acquisition of ARB per 1,000 antibiotic-days was 14 for carbapenems, 9 for glycopeptides, and 6 for broad-spectrum cephalosporins and quinolones. The highest rates of acquisition were observed for carbapenems in dialyzed and diabetic patients. Four risk factors were independently associated with acquisition of target ARB: use of carbapenems, age of >70 years, hospitalization for >16 days, and human immunodeficiency virus infection. During the 30-day follow-up, 4 among 42 patients newly colonized by ARB (9%) suffered from an infection due to the same bacteria as those isolated in a previous screening sample. Colonizing and infecting strains from single patients were genotypically identical. Identifying ARB colonization early during antibiotic therapy could target a high-risk hospitalized population that may benefit from intervention to decrease the risk of subsequent nosocomial infections.
Brain Penetration of Colistin in Mice Assessed by a Novel High-Performance Liquid Chromatographic Technique
Authors: Jin Liang , Li Jian , Nation Roger L. , Nicolazzo Joseph A. 
Published: August 2009

ABSTRACT

A sensitive and reliable liquid chromatographic method was developed and validated for the determination of colistin concentrations in mouse brain homogenate. With a mobile phase consisting of acetonitrile-tetrahydrofuran-water (50:25:25 [vol/vol]) at a flow rate of 1 ml/min, a linear correlation between peak area and colistin concentration was observed over the concentration range of 93.8 to 3,000 ng/g in brain tissue (
R
2
> 0.994). Intra- and interday coefficients of variation were 5.1 to 8.3% and 5.8 to 8.5%, respectively, and the recovery ranged from 85% to 94%. This assay was then utilized to determine the amount of colistin that permeated the blood-brain barrier over a 2-h period following bolus intravenous administration of colistin sulfate to mice. After a single dose of 5 mg/kg of body weight to mice, brain homogenate concentrations of colistin were very low, relative to plasma colistin concentrations, suggesting that colistin permeability across the healthy blood-brain barrier is negligible during this experimental period.
Body Weight Cutoff for Daily Dosage of Efavirenz and 60-Week Efficacy of Efavirenz-Based Regimen in Human Immunodeficiency Virus and Tuberculosis Coinfected Patients Receiving Rifampin
Authors: Manosuthi Weerawat , Sungkanuparph Somnuek , Tantanathip Preecha , Mankatitham Wiroj , Lueangniyomkul Aroon , Thongyen Supeda , Eampokarap Boonchuay , Uttayamakul Sumonmal , Suwanvattana Pawita , Kaewsaard Samroui , Ruxrungtham Kiat 
Published: August 2009

ABSTRACTSeventy-one human immunodeficiency virus-infected patients with tuberculosis who were receiving a rifampin (rifampicin)-containing regimen were initiated on treatment with efavirenz at 600 mg/day plus stavudine-lamivudine. Fasting efavirenz concentrations at 12 h after dosing (C12) were monitored. The mean ± standard deviation efavirenz C12at weeks 6 and 12 and after rifampin discontinuation were 4.5 ± 4.3, 3.8 ± 3.5, and 3.5 ± 2.7 mg/liter, respectively. High body weight was associated with a low efavirenz C12at weeks 6 and 12 (P= 0.003,r= −0.255). The efavirenz C12regression prediction line at 1 mg/liter intercepted a mean body weight of 57.5 kg.
Pharmacokinetics of Fosamprenavir plus Ritonavir in Human Immunodeficiency Virus Type 1-Infected Adult Subjects with Hepatic Impairment
Authors: Pérez-Elías María J. , Morellon María Larrousse , Ortega Enrique , Hernández-Quero José , Rodríguez-Torres Maribel , Clotet Bonaventura , Felizarta Franco , Gutiérrez Felix , Pineda Juan A. , Nichols Garrett , Lou Yu , Wire Mary Beth 
Published: August 2009

ABSTRACTThe effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (Cmax), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0-τ)], similar values for the concentration at the end of the dosing interval (Cτ), and 114% higher unboundCτvalues. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavirCmaxvalues, 27% lower AUC(0-24)values, 57% lowerCτvalues, and 21% higher unbound amprenavirCτvalues. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavirCmaxvalues, 23% lower AUC(0-24)values, 38% lowerCτvalues, and similar unbound amprenavirCτvalues. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24)values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.
Longitudinal Analysis of Raltegravir Susceptibility and Integrase Replication Capacity of Human Immunodeficiency Virus Type 1 during Virologic Failure
Authors: Fransen Signe , Karmochkine Marina , Huang Wei , Weiss Laurence , Petropoulos Christos J. , Charpentier Charlotte 
Published: August 2009

ABSTRACTWe characterized the raltegravir (RAL) susceptibility and the integrase (IN)-mediated replication capacity (RC) of RAL-resistant human immunodeficiency virus type 1 from two patients experiencing virologic failure during continuous RAL salvage therapy. The following two distinct outcomes were observed: (i) the selective outgrowth of virus with high-level RAL resistance and high IN-mediated RC leading to significant viral load rebound and (ii) the selection of virus with a slight reduction in RAL susceptibility and low IN-mediated RC resulting in sustained low-level viremia.
Antimalarial Activity of Simalikalactone E, a New Quassinoid from
Quassia amara
L. (Simaroubaceae)
Authors: Cachet N. , Hoakwie F. , Bertani S. , Bourdy G. , Deharo E. , Stien D. , Houel E. , Gornitzka H. , Fillaux J. , Chevalley S. , Valentin A. , Jullian V. 
Published: August 2009

ABSTRACT

We report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of
Quassia amara
L. (Simaroubaceae) leaves. This new molecule inhibited the growth of
Plasmodium falciparum
cultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from
Q. amara
, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of
Plasmodium vinckei petteri
by 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.
Aspergillus nidulans
Protein
O
-Mannosyltransferases Play Roles in Cell Wall Integrity and Developmental Patterning
Authors: Kriangkripipat Thanyanuch , Momany Michelle 
Published: August 2009

ABSTRACT

Protein
O
-mannosyltransferases (Pmts) initiate
O
-mannosyl glycan biosynthesis from Ser and Thr residues of target proteins. Fungal Pmts are divided into three subfamilies, Pmt1, -2, and -4.
Aspergillus nidulans
possesses a single representative of each Pmt subfamily,
pmtA
(subfamily 2),
pmtB
(subfamily 1), and
pmtC
(subfamily 4). In this work, we show that single Δ
pmt
mutants are viable and have unique phenotypes and that the Δ
pmtA
Δ
pmtB
double mutant is the only viable double mutant. This makes
A. nidulans
the first fungus in which all members of individual Pmt subfamilies can be deleted without loss of viability. At elevated temperatures, all
A. nidulans
Δ
pmt
mutants show cell wall-associated defects and increased sensitivity to cell wall-perturbing agents. The Δ
pmt
mutants also show defects in developmental patterning. Germ tube emergence is early in Δ
pmtA
and more frequent in Δ
pmtC
mutants than in the wild type. In Δ
pmtB
mutants, intrahyphal hyphae develop. All Δ
pmt
mutants show distinct conidiophore defects. The Δ
pmtA
strain has swollen vesicles and conidiogenous cells, the Δ
pmtB
strain has swollen conidiophore stalks, and the Δ
pmtC
strain has dramatically elongated conidiophore stalks. We also show that AN5660, an ortholog of
Saccharomyces cerevisiae
Wsc1p, is modified by PmtA and PmtC. The Δ
pmt
phenotypes at elevated temperatures, increased sensitivity to cell wall-perturbing agents and restoration to wild-type growth with osmoticum suggest that
A. nidulans
Pmts modify proteins in the cell wall integrity pathway. The altered developmental patterns in Δ
pmt
mutants suggest that
A. nidulans
Pmts modify proteins that serve as spatial cues.
Evolutionary Capture of Viral and Plasmid DNA by Yeast Nuclear Chromosomes
Authors: Frank A. Carolin , Wolfe Kenneth H. 
Published: August 2009

ABSTRACTA 10-kb region of the nuclear genome of the yeastVanderwaltozyma polysporacontains an unusual cluster of five pseudogenes homologous to five different genes from yeast killer viruses, killer plasmids, the 2μm plasmid, and aPenicilliumvirus. By further database searches, we show that this phenomenon is not unique toV. polysporabut that about 40% of the sequenced genomes of Saccharomycotina species contain integrated copies of genes from DNA plasmids or RNA viruses. We propose the name NUPAVs (nuclear sequences of plasmid and viral origin) for these objects, by analogy to NUMTs (nuclear copies of mitochondrial DNA) and NUPTs (nuclear copies of plastid DNA, in plants) of organellar origin. Although most of the NUPAVs are pseudogenes, one intact and active gene that was formed in this way is theKHS1chromosomal killer locus ofSaccharomyces cerevisiae. We show thatKHS1is a NUPAV related to M2 killer virus double-stranded RNA. Many NUPAVs are located beside tRNA genes, and some contain sequences from a mixture of different extrachromosomal sources. We propose that NUPAVs are sequences that were captured by the nuclear genome during the repair of double-strand breaks that occurred during evolution and that some of their properties may be explained by repeated breakage at fragile chromosomal sites.
Tricarboxylic Acid Cycle-Dependent Attenuation of
Staphylococcus aureus
In Vivo Virulence by Selective Inhibition of Amino Acid Transport
Authors: Zhu Yefei , Xiong Yan Q. , Sadykov Marat R. , Fey Paul D. , Lei Mei G. , Lee Chia Y. , Bayer Arnold S. , Somerville Greg A. 
Published: August 2009

ABSTRACT

Staphylococci are the leading causes of endovascular infections worldwide. Commonly, these infections involve the formation of biofilms on the surface of biomaterials. Biofilms are a complex aggregation of bacteria commonly encapsulated by an adhesive exopolysaccharide matrix. In staphylococci, this exopolysaccharide matrix is composed of polysaccharide intercellular adhesin (PIA). PIA is synthesized when the tricarboxylic acid (TCA) cycle is repressed. The inverse correlation between PIA synthesis and TCA cycle activity led us to hypothesize that increasing TCA cycle activity would decrease PIA synthesis and biofilm formation and reduce virulence in a rabbit catheter-induced model of biofilm infection. TCA cycle activity can be induced by preventing staphylococci from exogenously acquiring a TCA cycle-derived amino acid necessary for growth. To determine if TCA cycle induction would decrease PIA synthesis in
Staphylococcus aureus
, the glutamine permease gene (
glnP
) was inactivated and TCA cycle activity, PIA accumulation, biofilm forming ability, and virulence in an experimental catheter-induced endovascular biofilm (endocarditis) model were determined. Inactivation of this major glutamine transporter increased TCA cycle activity, transiently decreased PIA synthesis, and significantly reduced in vivo virulence in the endocarditis model in terms of achievable bacterial densities in biofilm-associated cardiac vegetations, kidneys, and spleen. These data confirm the close linkage of TCA cycle activity and virulence factor production and establish that this metabolic linkage can be manipulated to alter infectious outcomes.
Cytotoxicity and Secretion of Gamma Interferon Are Carried Out by Distinct CD8 T Cells duringMycobacterium tuberculosisInfection
Authors: Einarsdottir Thorbjorg , Lockhart Euan , Flynn JoAnne L. 
Published: August 2009

ABSTRACTThe host immune response is generally sufficient to containMycobacterium tuberculosisinfection. It does not, however, efficiently prevent subsequent infection withM. tuberculosisor provide sterilizing immunity. While the understanding of the immune response generated against this pathogen is incomplete, improvements have been achieved due to advances in immunological tools. In this study, we analyzed the multifunctional nature of primary and memory CD8 T-cell responses generated during murineM. tuberculosisinfection. We generated a recombinantM. tuberculosisstrain expressing ovalbumin (OVA) epitopes in order to expand the peptides for the detection of CD8 T cells duringM. tuberculosisinfection and enable us to use OVA-specific reagents. Our results indicate that the majority ofM. tuberculosis-specific CD8 T cells are limited to either cytotoxicity or the secretion of gamma interferon (IFN-γ), with cytotoxicity being far more prevalent than IFN-γ secretion. Memory CD8 T cells responded earlier and reached higher levels in the lungs than naïve CD8 T cells, as was expected. They were, however, less cytotoxic and secreted less IFN-γ than newly primed CD8 T cells, suggesting that one factor contributing to bacterial persistence and lack of sterilizing immunity may be the low quality of memory cells that are generated.
RecombinantListeria monocytogenesExpressing a Cell Wall-Associated Listeriolysin O Is Weakly Virulent but Immunogenic
Authors: Carrero Javier A. , Calderon Boris , Vivanco-Cid Hector , Unanue Emil R. 
Published: August 2009

ABSTRACTListeriolysin O (LLO) is an essential virulence factor for the gram-positive bacteriumListeria monocytogenes. Our goal was to determine if altering the topology of LLO would alter the virulence and toxicity ofL. monocytogenesin vivo. A recombinant strain was generated that expressed a surface-associated LLO (sLLO) variant secreted at 40-fold-lower levels than the wild type. In culture, the sLLO strain grew in macrophages, translocated to the cytosol, and induced cell death. However, the sLLO strain showed decreased infectivity, reduced lymphocyte apoptosis, and decreased virulence despite a normal in vitro phenotype. Thus, the topology of LLO inL. monocytogeneswas a factor in the pathogenesis of the infection and points to a role of LLO secretion during in vivo infection. The sLLO strain was cleared by severe combined immunodeficient (SCID) mice. Despite the attenuation of virulence, the sLLO strain was immunogenic and capable of eliciting protective T-cell responses.
A Comparative Genomics, Network-Based Approach to Understanding Virulence in
Vibrio cholerae
Authors: Gu Jianying , Wang Yufeng , Lilburn Timothy 
Published: August 2009

ABSTRACT

Our views of the genes that drive phenotypes have generally been built up one locus or operon at a time. However, a given phenotype, such as virulence, is a multilocus phenomenon. To gain a more comprehensive view of the genes and interactions underlying a phenotype, we propose an approach that incorporates information from comparative genomics and network biology and illustrate it by examining the virulence phenotype of
Vibrio cholerae
O1 El Tor N16961. We assessed the associations among the virulence-associated proteins from
Vibrio cholerae
and all the other proteins from this bacterium using a functional-association network map. In the context of this map, we were able to identify 262 proteins that are functionally linked to the virulence-associated genes more closely than is typical of the proteins in this strain and 240 proteins that are functionally linked to the virulence-associated proteins with a confidence score greater than 0.9. The roles of these genes were investigated using functional information from online data sources, comparative genomics, and the relationships shown by the protein association map. We also incorporated core proteome data from the family
Vibrionaceae
; 35% of the virulence-associated proteins have orthologs among the 1,822 orthologous groups of proteins in the core proteome, indicating that they may be dual-role virulence genes or encode functions that have value outside the human host. This approach is a valuable tool in searching for novel functional associations and in investigating the relationship between genotype and phenotype.