bluuebunny/crossref_metadata_2025_split huggingface dataset:
First Report of Plasmid-Mediated Quinolone Resistance Determinant
qnrS1
in an
Escherichia coli
Strain of Animal Origin in Italy
Authors: Cerquetti Marina , García-Fernández Aurora , Giufrè Maria , Fortini Daniela , Accogli Marisa , Graziani Caterina , Luzzi Ida , Caprioli Alfredo , Carattoli Alessandra 
Published: May 2009

ABSTRACT

A
qnrS1
-positive strain of
Escherichia coli
was detected among 73 poultry isolates showing ciprofloxacin MICs of ≥0.125 μg/ml. The
qnrS1
gene was associated with a Tn
3
-like transposon, as previously described to occur in a
Salmonella enterica
serovar Infantis strain of animal origin, but the plasmid scaffold carrying this element resembled that of a plasmid previously identified in
Salmonella enterica
serovar Dublin. These elements suggest genetic exchanges among
Salmonella
and
E. coli
and a potential animal reservoir for the
qnr
genes.
Efficacy of Liposomal Amphotericin B Combined with Gamma Interferon or Granulocyte-Macrophage Colony-Stimulating Factor for Treatment of Systemic Zygomycosis in Mice
Authors: Rodríguez M. Mar , Calvo Enrique , Mariné Marçal , Pastor F. Javier , Fernandez-Ballart Joan , Guarro Josep 
Published: May 2009

ABSTRACT

Granulocyte-macrophage colony-stimulating factor enhanced the efficacy of liposomal amphotericin B (LAMB) in a murine model of disseminated infection by
Rhizopus oryzae
, significantly prolonging survival and reducing tissue burden. The use of gamma interferon (IFN-γ) alone was ineffective, and IFN-γ combined with LAMB did not improve the results obtained with LAMB alone.
Pharmacokinetics and Pharmacodynamics of a Novel Triazole, Isavuconazole: Mathematical Modeling, Importance of Tissue Concentrations, and Impact of Immune Status on Antifungal Effect
Authors: Warn Peter A. , Sharp Andrew , Parmar Arvind , Majithiya Jayesh , Denning David W. , Hope William W. 
Published: May 2009

ABSTRACT
Isavuconazole is a triazole with broad-spectrum activity against medically important fungal pathogens. We investigated the pharmacokinetics and pharmacodynamics of isavuconazole in a murine model of disseminated candidiasis. We determined the pharmacokinetics in both plasma and kidney. The relationship between tissue concentrations and the resultant antifungal effect was described using a mathematical model. The pharmacodynamic parameter that optimally links drug exposure with the antifungal effect was determined using dose fractionation studies. The impact of the immune status of mice receiving isavuconazole was determined in persistently and temporarily neutropenic animals. The pharmacokinetics of 1.6 to 28 mg isavuconazole/kg of body weight were linear. Exposure-response relationships demonstrated near-maximal effect following the administration of >15 mg/kg. The mathematical model showed that exposures in the kidney were 5.77 times higher than those in plasma, and there was persistence of the drug at this site despite concentrations in plasma falling to undetectable levels. The in vitro and in vivo postantifungal effects were 2 to 5 and 8.41 h, respectively. The area under the concentration-time curve (AUC)/MIC ratio was the parameter that optimally linked drug exposure with the observed antifungal effect. The total drug AUC/MIC ratios associated with a 90% probability of survival in temporarily and persistently neutropenic mice were 270 and 670, respectively. Once corrected for protein binding, these values are similar to the magnitude of drug exposure associated with a high probability of a successful therapeutic outcome for other triazoles. This study provides the experimental foundation for the use of isavuconazole in patients with disseminated candidiasis.
Light-Microscopic Immunocytochemistry for Gentamicin and Its Use for Studying Uptake of the Drug in Kidney
Authors: Fujiwara Kunio , Shin Masashi , Matsunaga Hayato , Saita Tetsuya , Larsson Lars-Inge 
Published: May 2009

ABSTRACTGentamicin (GM) is a widely used antibiotic but shows renal toxicity. We produced a serum against GM (anti-GM) conjugated to bovine serum albumin withN-(gamma-maleimidobutyryloxy)succinimide. The antiserum was monospecific for GM and did not cross-react with the analog streptomycin, tobramycin, kanamycin, or amikacin. The antiserum also detected glutaraldehyde-fixed GM, and this enabled us to develop an immunocytochemical method for detecting the uptake of GM in rat kidney. Twelve hours after a single intravenous administration of GM, immunocytochemistry revealed that GM accumulated in the S1, S2, and S3 segments of the proximal tubules, as well as in the distal tubules and collecting ducts. By 12 h after injection, the drug was detected in cytoplasmic granules of the proximal tubule cells. However, early (1 h) after injection, drug accumulation was detected in the microvilli of these cells. The distal tubules and collecting ducts contained scattered swollen cells, reminiscent of necrotic cells, in which both the nuclei and the cytoplasm reacted strongly with GM. No staining occurred in the kidneys of saline-injected control rats. These results agree with previous studies showing that GM is endocytosed in the proximal tubules and accumulates in lysosomes. Additionally, our results show that GM also accumulates in the distal tubules and collecting ducts. This was achieved by systematically varying the pretreatment conditions—an approach necessary for detecting GM in different subcellular compartments. This approach should be useful for accurately detecting the uptake and toxicity of the antibiotic in different tissues.
Pharmacokinetics of Intravenous Piperacillin Administration in Patients Undergoing On-Line Hemodiafiltration
Authors: Oh Kook-Hwan , Kim Chiweon , Lee Hankyu , Lee Hajeong , Jung Ji Yong , Kim Nam Joong , Yu Kyung-Sang , Shin Kwang-Hee , Jang In-Jin , Ahn Curie 
Published: May 2009

ABSTRACT
The pharmacokinetic characteristics of piperacillin sodium were studied in five volunteers undergoing on-line hemodiafiltration (HDF). The subjects were given 2 g of piperacillin sodium intravenously over 1 min and placed on on-line HDF for 4 h starting at 60 min after the piperacillin infusion. Noncompartmental models were employed for estimation of the pharmacokinetic parameters, and intradialytic piperacillin clearance was calculated by the recovery method. The mean volume of distribution and the elimination half-life were 0.27 ± 0.13 liter/kg (mean ± standard deviation) and 1.1 ± 0.6 h, respectively. The total body clearance of piperacillin was 0.19 ± 0.08 liter/h/kg. Piperacillin clearance through on-line HDF was 0.11 ± 0.06 liter/h/kg. The mean serum piperacillin concentration was 4.0 ± 1.9 μg/ml at the end of the 4-h on-line HDF session. The concentration of infused piperacillin recovered in the dialysate was 527 ± 236 mg (26.3% ± 11.8%). We suggest the replacement of 500 mg of piperacillin after each on-line HDF session.
Inhibitory Effects of Lactoferrin on Growth and Biofilm Formation ofPorphyromonas gingivalisandPrevotella intermedia
Authors: Wakabayashi Hiroyuki , Yamauchi Koji , Kobayashi Tetsuo , Yaeshima Tomoko , Iwatsuki Keiji , Yoshie Hiromasa 
Published: May 2009

ABSTRACTLactoferrin (LF) is an iron-binding antimicrobial protein present in saliva and gingival crevicular fluids, and it is possibly associated with host defense against oral pathogens, including periodontopathic bacteria. In the present study, we evaluated the in vitro effects of LF-related agents on the growth and biofilm formation of two periodontopathic bacteria,Porphyromonas gingivalisandPrevotella intermedia, which reside as biofilms in the subgingival plaque. The planktonic growth ofP. gingivalisandP. intermediawas suppressed for up to 5 h by incubation with ≥130 μg/ml of human LF (hLF), iron-free and iron-saturated bovine LF (apo-bLF and holo-bLF, respectively), and ≥6 μg/ml of bLF-derived antimicrobial peptide lactoferricin B (LFcin B); but those effects were weak after 8 h. The biofilm formation ofP. gingivalisandP. intermediaover 24 h was effectively inhibited by lower concentrations (≥8 μg/ml) of various iron-bound forms (the apo, native, and holo forms) of bLF and hLF but not LFcin B. A preformed biofilm ofP. gingivalisandP. intermediawas also reduced by incubation with various iron-bound bLFs, hLF, and LFcin B for 5 h. In an examination of the effectiveness of native bLF when it was used in combination with four antibiotics, it was found that treatment with ciprofloxacin, clarithromycin, and minocycline in combination with native bLF for 24 h reduced the amount of a preformed biofilm ofP. gingivaliscompared with the level of reduction achieved with each agent alone. These results demonstrate the antibiofilm activity of LF with lower iron dependency againstP. gingivalisandP. intermediaand the potential usefulness of LF for the prevention and treatment of periodontal diseases and as adjunct therapy for periodontal diseases.
Pharmacokinetics and Safety Profile of the Human Anti-
Pseudomonas aeruginosa
Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers
Authors: Lazar Hedvika , Horn Michael P. , Zuercher Adrian W. , Imboden Martin A. , Durrer Peter , Seiberling Michael , Pokorny Rolf , Hammer Christophe , Lang Alois B. 
Published: May 2009

ABSTRACT

KBPA-101 is a human monoclonal antibody of the immunoglobulin M isotype, which is directed against the O-polysaccharide moiety of
Pseudomonas aeruginosa
serotype O11. This double-blind, dose escalation study evaluated the safety and pharmacokinetics of KBPA-101 in 32 healthy volunteers aged 19 to 46 years. Each subject received a single intravenous infusion of KBPA-101 at a dose of 0.1, 0.4, 1.2, or 4 mg/kg of body weight or placebo infused over 2 h. Plasma samples for pharmacokinetic assessments were taken before infusion as well as 0.25, 0.5, 1, 2, 2.5, 4, 6, 8, 12, 24, 36, and 48 h and 4, 7, 10, and 14 days after start of dosing. Plasma concentrations of KBPA-101 were detected with mean maximum concentrations of drug in plasma of 1,877, 7,571, 24,923, and 83,197 ng/ml following doses of 0.1, 0.4, 1.2, and 4.0 mg/kg body weight, respectively. The mean elimination half-life was between 70 and 95 h. The mean volume of distribution was between 4.76 and 5.47 liters. Clearance ranged between 0.039 and 0.120 liters/h. At the highest dose of 4.0 mg/kg, plasma KBPA-101 levels were greater than 5,000 ng/ml for 14 days. KBPA-101 exhibited linear kinetics across all doses. No anti-KBPA-101 antibodies were detected after dosing in any subject. Overall, the human monoclonal antibody KBPA-101 was well tolerated over the entire dose range in healthy volunteers, and no serious adverse events have been reported.
The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100
Authors: Murakami Tsutomu , Kumakura Sei , Yamazaki Toru , Tanaka Reiko , Hamatake Makiko , Okuma Kazu , Huang Wei , Toma Jonathan , Komano Jun , Yanaka Mikiro , Tanaka Yuetsu , Yamamoto Naoki 
Published: May 2009

ABSTRACT

The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1α binding to CXCR4 and Ca
2+
signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
Saccharomyces cerevisiae
Rbg1 Protein and Its Binding Partner Gir2 Interact on Polyribosomes with Gcn1
Authors: Wout P. K. , Sattlegger E. , Sullivan S. M. , Maddock J. R. 
Published: May 2009

ABSTRACT

Rbg1 is a previously uncharacterized protein of
Saccharomyces cerevisiae
belonging to the Obg/CgtA subfamily of GTP-binding proteins whose members are involved in ribosome function in both prokaryotes and eukaryotes. We show here that Rbg1 specifically associates with translating ribosomes. In addition, in this study proteins were identified that interact with Rbg1 by yeast two-hybrid screening and include Tma46, Ygr250c, Yap1, and Gir2. Gir2 contains a GI (
G
cn2 and
I
mpact) domain similar to that of Gcn2, an essential factor of the general amino acid control pathway required for overcoming amino acid shortage. Interestingly, we found that Gir2, like Gcn2, interacts with Gcn1 through its GI domain, and overexpression of Gir2, under conditions mimicking amino acid starvation, resulted in inhibition of growth that could be reversed by Gcn2 co-overexpression. Moreover, we found that Gir2 also cofractionated with polyribosomes, and this fractionation pattern was partially dependent on the presence of Gcn1. Based on these findings, we conclude that Rbg1 and its interacting partner Gir2 associate with ribosomes, and their possible biological roles are discussed.
The Capsule-Encoding
viaB
Locus Reduces Intestinal Inflammation by a
Salmonella
Pathogenicity Island 1-Independent Mechanism
Authors: Haneda Takeshi , Winter Sebastian E. , Butler Brian P. , Wilson R. Paul , Tükel Çagla , Winter Maria G. , Godinez Ivan , Tsolis Renée M. , Bäumler Andreas J. 
Published: May 2009

ABSTRACT

Salmonella enterica
serotype Typhimurium elicits acute neutrophil influx in the human intestinal mucosa within 1 or 2 days after infection, resulting in inflammatory diarrhea. In contrast, no overt symptoms are observed within the first 1 or 2 weeks after infection with
S. enterica
serotype Typhi. Here we show that introduction of the capsule-encoding
viaB
locus of serotype Typhi reduced the ability of serotype Typhimurium to elicit acute intestinal inflammation in a streptomycin-pretreated mouse model. Serotype Typhimurium requires a functional invasion-associated type III secretion system (type III secretion system 1 [T3SS-1]) to elicit cecal inflammation within 48 h after infection of streptomycin-pretreated mice, and the presence of the
viaB
locus reduced its invasiveness for human intestinal epithelial cells in vitro. However, a reduced activity of T3SS-1 could not account for the ability of the
viaB
locus to attenuate cecal inflammation, because introduction of the
viaB
locus into an invasion-deficient serotype Typhimurium strain (
invA
mutant) resulted in a significant reduction of pathology and inflammatory cytokine expression in the cecum 5 days after infection of mice. We conclude that a T3SS-1-independent mechanism contributes to the ability of the
viaB
locus to reduce intestinal inflammation.
CspA-Mediated Binding of Human Factor H Inhibits Complement Deposition and Confers Serum Resistance in
Borrelia burgdorferi
Authors: Kenedy Melisha R. , Vuppala Santosh R. , Siegel Corinna , Kraiczy Peter , Akins Darrin R. 
Published: May 2009

ABSTRACT

Borrelia burgdorferi
has developed efficient mechanisms for evading the innate immune response during mammalian infection and has been shown to be resistant to the complement-mediated bactericidal activity of human serum. It is well recognized that
B. burgdorferi
expresses multiple lipoproteins on its surface that bind the human complement inhibitors factor H and factor H-like protein 1 (FH/FHL-1). The binding of FH/FHL-1 on the surface of
B. burgdorferi
is thought to enhance its ability to evade serum-mediated killing during the acute phase of infection. One of the key
B. burgdorferi
FH/FHL-1 binding proteins identified thus far was designated CspA. While it is known that CspA binds FH/FHL-1, it is unclear how the interaction between CspA and FH/FHL-1 specifically enhances serum resistance. To better understand how CspA mediates serum resistance in
B. burgdorferi
, we inactivated
cspA
in a virulent strain of
B. burgdorferi
. An affinity ligand blot immunoassay and indirect immunofluorescence revealed that the CspA mutant does not efficiently bind human FH to its surface. Consistent with the lack of FH binding, the CspA mutant was also highly sensitive to killing by human serum. Additionally, the deposition of complement components C3, C6, and C5b-9 was enhanced on the surface of the CspA mutant compared to that of the wild-type strain. The combined data lead us to conclude that the CspA-mediated binding of human FH confers serum resistance by directly inhibiting complement deposition on the surface of
B. burgdorferi
.
Identification of a Simple Chemical Structure Associated with Protective Human Antibodies against Multiple Pneumococcal Serogroups
Authors: Park Saeyoung , Parameswar Archana R. , Demchenko Alexei V. , Nahm Moon H. 
Published: May 2009

ABSTRACTStreptococcus pneumoniae, a major human pathogen, expresses at least 91 serologically distinct carbohydrate capsules. Since pneumococcal vaccines are designed to elicit antibodies against many different capsular polysaccharides (PSs), it is important to identify the epitopes involved in eliciting anti-capsular PS antibodies. We investigated the epitopes recognized by Dob1, which is a hybridoma-secreting human immunoglobulin G2 antibody to the PS of serotype 6B (Y. Sun et al., Infect. Immun. 67:1172-1179, 1999). We found that Dob1 bound synthetic capsular carbohydrates Gal(1→3)α-d-Glcp(1→3)α-l-Rhap(1→3)Rib-ol and α-d-Glcp(1→3)α-l-Rhap(1→3)Rib-ol but did not bind α-l-Rhap(1→3)Rib-ol. The critical epitope α-d-Glcp(1→3)α-l-Rhapis found in the capsular PSs of serotypes 6A, 6B, 6C, and 19A but not in the 19F PS. Consistent with this observation, Dob1 bound to the PSs of serotypes 6A, 6B, 6C, and 19A but did not bind the 19F PS and 23 additional unrelated pneumococcal capsular PSs. Also, Dob1 could opsonize pneumococci expressing serotypes 6A, 6B, 6C, and 19A but did not opsonize 19F pneumococci. In addition, ca. 7% of immune sera (12 of 175 sera) had significant amounts of Dob1-like antibodies, i.e., reacted with 6B and 19A PSs, but not with 19F PS. Humans can produce antibodies to the Dob1 epitope and the antibodies to that epitope cross-react with the four serotypes 6A, 6B, 6C, and 19A that belong to different serogroups. This epitope may be useful for producing a totally synthetic, simple chemical structure that is capable of generating protective antibodies to multiple pneumococcal serogroups.
Urothelial Cultures Support Intracellular Bacterial Community Formation by UropathogenicEscherichia coli
Authors: Berry Ruth E. , Klumpp David J. , Schaeffer Anthony J. 
Published: May 2009

ABSTRACTUropathogenicEscherichia coli(UPEC) causes most community-acquired and nosocomial urinary tract infections (UTI). In a mouse model of UTI, UPEC invades superficial bladder cells and proliferates rapidly, forming biofilm-like structures called intracellular bacterial communities (IBCs). Using a gentamicin protection assay and fluorescence microscopy, we developed an in vitro model for studying UPEC proliferation within immortalized human urothelial cells. By pharmacologic manipulation of urothelial cells with the cholesterol-sequestering drug filipin, numbers of intracellular UPEC CFU increased 8 h and 24 h postinfection relative to untreated cultures. Enhanced UPEC intracellular proliferation required that the urothelial cells, but not the bacteria, be filipin treated prior to infection. However, neither UPEC frequency of invasion nor early intracellular trafficking events to a Lamp1-positive compartment were modulated by filipin. Upon inspection by fluorescence microscopy, cultures with enhanced UPEC intracellular proliferation exhibited large, dense bacterial aggregates within cells that resembled IBCs but were contained with Lamp1-positive vacuoles. While an isogenicfimHmutant was capable of forming these IBC-like structures, the mutant formed significantly fewer than wild-type UPEC. Similar to IBCs, expression ofE. coliiron acquisition systems was upregulated by intracellular UPEC. Expression of other putative virulence factors, includinghlyA,cnf1,fliC,kpsD, and the biofilm adhesinyfaLalso increased, while expression offimAdecreased and that offludid not change. These results indicate that UPEC differentially regulates virulence factors in the intracellular environment. Thus, immortalized urothelial cultures that recapitulate IBC formation in vitro represent a novel system for the molecular and biochemical characterization of the UPEC intracellular life cycle.
Chlamydial and Periodontal Pathogens Induce Hepatic Inflammation and Fatty Acid Imbalance in Apolipoprotein E-Deficient Mice
Authors: Hyvärinen Kati , Tuomainen Anita M. , Laitinen Saara , Bykov Igor L. , Törmäkangas Liisa , Lindros Kai , Käkelä Reijo , Alfthan Georg , Salminen Irma , Jauhiainen Matti , Kovanen Petri T. , Leinonen Maija , Saikku Pekka , Pussinen Pirkko J. 
Published: May 2009

ABSTRACT

Periodontitis and
Chlamydia pneumoniae
infection are independent risk factors for cardiovascular diseases. The aim of this study was to investigate the effect of
C. pneumoniae
and
Aggregatibacter actinomycetemcomitans
infection on hepatic inflammation and lipid homeostasis of apolipoprotein E-deficient mice. Mice were infected with viable
C. pneumoniae
intranasally three times for chronic infection or once for acute infection. Viable
A. actinomycetemcomitans
was administered 10 times intravenously alone or in concert with
C. pneumoniae
. Hepatic alterations were assessed by histochemistry, lipid quantification, and fatty acid profile analysis. The RNA expression levels and the presence of pathogens in the livers and lungs were detected by quantitative real-time PCR. Both pathogens were detected in the livers of the infected animals. Chronic
C. pneumoniae
infection induced marked changes in hepatic lipid homeostasis.
A. actinomycetemcomitans
infection resulted in inflammatory cell infiltration into the liver, accompanied by elevated hepatic RNA expression levels of inflammation-related genes and higher serum amyloid A and lipopolysaccharide concentrations. Our results indicate that proatherogenic pathogens infect the liver, causing proinflammatory alterations and lipid disturbances. This infection may maintain chronic systemic inflammation attributable to atherogenesis.