bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Interferon Inducer Ampligen [Poly(I)-Poly(C
12
U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis
Authors: Padalko Elizaveta , Nuyens Dieter , De Palma Armando , Verbeken Erik , Aerts Joeri L. , De Clercq Erik , Carmeliet Peter , Neyts Johan 
Published: December 2003

ABSTRACT

Viral replication, as well as an immunopathological component, is assumed to be involved in coxsackie B virus-induced myocarditis. We evaluated the efficacy of the interferon inducer Ampligen on coxsackie B3 virus-induced myocarditis in C3H/HeNHsd mice. The efficacy of Ampligen was compared with that of the interferon inducer poly(inosinic acid)-poly(cytidylic acid) [poly(IC)], alpha interferon 2b (INTRON A), and pegylated alpha interferon 2b (PEG-INTRON-α-2b). Ampligen at 20 mg/kg of body weight/day was able to reduce the severity of virus-induced myocarditis, as assessed by morphometric analysis, by 98% (
P
= 3.0 × 10
−8
). When poly(IC) was administered at 15 mg/kg/day, it reduced the severity of virus-induced myocarditis by 93% (
P
= 5.6 × 10
−5
). Alpha interferon 2b (1 × 10
5
U/day) and pegylated alpha interferon 2b (5 × 10
5
U/day) were less effective and reduced the severity of virus-induced myocarditis by 66% (
P
= 0.0009) and 78% (
P
= 0.0002), respectively. The observed efficacies of Ampligen and poly(IC) were corroborated by the observation that the drugs also markedly reduced the virus titers in the heart, as detected by (i) quantitative real-time reverse transcription-PCR and (ii) titration for infectious virus content. Whereas the electrocardiograms for untreated mice with myocarditis were severely disturbed, the electrocardiographic parameters were normalized in Ampligen- and poly(IC)-treated mice. Even when start of treatment with Ampligen was delayed until day 2 postinfection, a time at which lesions had already appeared in untreated control animals, a marked protective effect on the development of viral myocarditis (as assessed at day 6 postinfection) was still noted.
Vancomycin-Resistant
Staphylococcus aureus
Isolate from a Patient in Pennsylvania
Authors: Tenover Fred C. , Weigel Linda M. , Appelbaum Peter C. , McDougal Linda K. , Chaitram Jasmine , McAllister Sigrid , Clark Nancye , Killgore George , O'Hara Caroline M. , Jevitt Laura , Patel Jean B. , Bozdogan Bülent 
Published: December 2003

ABSTRACT

A vancomycin-resistant
Staphylococcus aureus
(VRSA) isolate was obtained from a patient in Pennsylvania in September 2002. Species identification was confirmed by standard biochemical tests and analysis of 16S ribosomal DNA,
gyrA
, and
gyrB
sequences; all of the results were consistent with the
S. aureus
identification. The MICs of a variety of antimicrobial agents were determined by broth microdilution and macrodilution methods following National Committee for Clinical Laboratory Standards (NCCLS) guidelines. The isolate was resistant to vancomycin (MIC = 32 μg/ml), aminoglycosides, β-lactams, fluoroquinolones, macrolides, and tetracycline, but it was susceptible to linezolid, minocycline, quinupristin-dalfopristin, rifampin, teicoplanin, and trimethoprim-sulfamethoxazole. The isolate, which was originally detected by using disk diffusion and a vancomycin agar screen plate, was vancomycin susceptible by automated susceptibility testing methods. Pulsed-field gel electrophoresis (PFGE) of
Sma
I-digested genomic DNA indicated that the isolate belonged to the USA100 lineage (also known as the New York/Japan clone), the most common staphylococcal PFGE type found in hospitals in the United States. The VRSA isolate contained two plasmids of 120 and 4 kb and was positive for
mecA
and
vanA
by PCR amplification. The
vanA
sequence was identical to the
vanA
sequence present in Tn
1546
. A DNA probe for
vanA
hybridized to the 120-kb plasmid. This is the second VRSA isolate reported in the United States.
Linezolid Pharmacokinetics in Adult Patients with Cystic Fibrosis
Authors: Bosso John A. , Flume Patrick A. , Gray Susan L. 
Published: December 2003

ABSTRACT

The pharmacokinetics of many drugs are altered in patients with cystic fibrosis (CF), often necessitating different dosage requirements than those used in non-CF patients. The objective of this study was to determine the pharmacokinetics of linezolid, an antibiotic with good activity against gram-positive organisms such as methicillin-resistant
Staphylococcus aureus
, in patients with CF so that dosage requirements could be established. Twelve adult patients (6 male) ranging in age from 22 to 39 years were studied. A single 600-mg dose was administered intravenously over 0.5 h, and plasma samples were collected at 0 (predose), 0.5, 0.75, 1, 2, 4, 8, and 24 h. Linezolid concentrations were determined with a validated high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using standard noncompartmental methods. Blood chemistry and hematologic indices were determined before and after the study for safety purposes. All patients completed the study without encountering any adverse reactions. The pharmacokinetic parameters, while variable, with half-lives varying from 1.76 to 8.36 h, were similar to those previously described in other populations. Mean (± standard deviation) values for pharmacokinetic parameters of interest were as follows: elimination rate constant, 0.21 (0.11) h
−1
; half-life, 4.41 (2.43); volume of distribution at steady state, 0.87 (0.19) liters/kg of body weight; and total body clearance, 0.12 (0.06) liters/h/kg. No patient would have achieved the pharmacodynamic target of an area under the concentration-time curve/MIC ratio of 83 h for pathogens for which the MIC was 4 μg/ml. Patients with inadequate clinical responses to linezolid may require more frequent dosing.
Local Variants of Staphylococcal Cassette Chromosome
mec
in Sporadic Methicillin-Resistant
Staphylococcus aureus
and Methicillin-Resistant Coagulase-Negative Staphylococci: Evidence of Horizontal Gene Transfer?
Authors: Hanssen Anne-Merethe , Kjeldsen Gry , Sollid Johanna U. Ericson 
Published: December 2003

ABSTRACT

The
mecA
gene in
Staphylococcus aureus
is located on the genetic element staphylococcal cassette chromosome (SCC). Different SCC
mec
s have been classified according to their putative recombinase genes (
ccrA
and
ccrB
) and overall genetic composition. Clinical isolates of coagulase-negative staphylococci (CoNS;
n
= 39) and
S. aureus
(
n
= 20) from Norway, India, Italy, Finland, the United States, and the United Kingdom were analyzed by pulsed-field gel electrophoresis, which showed that most isolates were genetically unrelated. Cluster analyses of 16S rRNA gene and
pta
sequences confirmed the traditional biochemical species identification. The
mecI
,
mecR1
,
mecA
, and
ccrAB
genes were detected by PCRs, identifying 19 out of 20
S. aureus
and 17 out of 39 CoNS isolates as carriers of one of the three published
ccrAB
pairs. New variants of SCC
mec
were identified, as well as CoNS isolates containing
ccrAB
genes without the
mec
locus.
ccrAB
and
mec
PCRs were verified by hybridization. Sequence alignments of
ccrAB
genes showed a high level of diversity between the
ccrAB
alleles from different isolates, i.e., 94 to 100% and 95 to 100% homology for
ccrAB1
and
ccrAB2
, respectively. All of the
ccrAB3
genes identified were identical. Genetically unique and sporadic methicillin-resistant
S. aureus
(MRSA) contained local variants of
ccrAB
gene pairs identical to those found in MR-CoNS but different from those in MRSA from other regions. Allelic variants of
ccrAB
in isolates from the same geographic region showed sequence conservation independent of species. The species-independent sequence conservation found suggests that there is a closer genetic relationship between
ccrAB2
in Norwegian staphylococci than between
ccrAB2
sequences in international MRSA and Norwegian MRSA. This might indicate that different staphylococcal species acquire these genes locally by horizontal gene transfer.
Pyridines and Pyrimidines Mediating Activity against an Efflux-Negative Strain of
Candida albicans
through Putative Inhibition of Lanosterol Demethylase
Authors: Buurman Ed T. , Blodgett April E. , Hull Kenneth G. , Carcanague Daniel 
Published: December 2003

ABSTRACT

The first step in ergosterol biosynthesis in
Saccharomyces cerevisiae
consists of the condensation of two acetyl coenzyme A (acetyl-CoA) moieties by acetoacetyl-CoA thiolase, encoded by
ERG10
. The inhibition of the sterol pathway results in feedback activation of
ERG10
transcription. A cell-based reporter assay, in which increased
ERG10
transcription results in elevated specific β-galactosidase activity, was used to find novel inhibitors of ergosterol biosynthesis that could serve as chemical starting points for the development of novel antifungal agents. A class of pyridines and pyrimidines identified in this way had no detectable activity against the major fungal pathogen
Candida albicans
(MICs > 64 μg · ml
−1
). However, a strain of
C. albicans
lacking the Cdr1p and Cdr2p efflux pumps was sensitive to the compounds (with MICs ranging from 2 to 64 μg · ml
−1
), suggesting that they are efficiently removed from wild-type cells. Quantitative analysis of sterol intermediates that accumulated during growth inhibition revealed the accumulation of lanosterol at the expense of ergosterol. Furthermore, a clear correlation was found between the 50% inhibitory concentration at which the sterol profile was altered and the antifungal activity, measured as the MIC. This finding strongly suggests that the inhibition of growth was caused by a reduction in ergosterol synthesis. The compounds described here are a novel class of antifungal pyridines and pyrimidines and the first pyri(mi)dines to be shown to putatively mediate their antifungal activity against
C. albicans
via lanosterol demethylase.
In Vitro Activities of Tigecycline against Erythromycin-Resistant
Streptococcus pyogenes
and
Streptococcus agalactiae
: Mechanisms of Macrolide and Tetracycline Resistance
Authors: Betriu C. , Culebras E. , Rodríguez-Avial I. , Gómez M. , Sánchez B. A. , Picazo J. J. 
Published: December 2003

ABSTRACT

The activity of tigecycline was tested against erythromycin-resistant streptococci (107
Streptococcus pyogenes
and 98
Streptococcus agalactiae
strains). The presence of erythromycin and tetracycline resistance genes was determined by PCR. Among
S. pyogenes
strains the most prevalent gene was
mef
(A) (91.6%). The
erm
(B) gene was the most prevalent (65.3%) among
S. agalactiae
strains. Tigecycline proved to be very active against all the isolates tested (MIC at which 90% of the isolates tested were inhibited, 0.06 μg/ml), including those resistant to tetracycline.
bla
VIM-7
, an Evolutionarily Distinct Metallo-β-Lactamase Gene in a
Pseudomonas aeruginosa
Isolate from the United States
Authors: Toleman Mark A. , Rolston Kenneth , Jones Ronald N. , Walsh Timothy R. 
Published: December 2003

ABSTRACT

As part of the CANCER Antimicrobial Surveillance Program in North America, a
Pseudomonas aeruginosa
isolate, strain 07-406, was shown to possess a metallo-β-lactamase, designated VIM-7.
bla
VIM-7
is located on a 24-kb plasmid which can be readily transferred into
Enterobacteriaceae
and other pseudomonads. This is the first report of a mobile metallo-β-lactamase gene,
bla
VIM-7
, being detected within the United States.
Comparison of In Vitro Activities of Ketolides, Macrolides, and an Azalide against the SpirocheteBorrelia burgdorferi
Authors: Hunfeld Klaus-Peter , Wichelhaus Thomas A. , Rödel Rebecca , Acker Georg , Brade Volker , Kraiczy Peter 
Published: December 2003

ABSTRACTTwo ketolides, three macrolides, and one azalide were tested in vitro against 17 isolates of theB. burgdorferis.l. complex. As measured in micrograms per milliliter, activity was highest for cethromycin (MIC at which 90% of the tested isolates were inhibited [MIC90], 0.0019 μg/ml) and telithromycin (MIC90, 0.0078 μg/ml). Electron-microscope analysis and time-kill studies also supported enhanced effectiveness of both ketolides.
Chromosome-Encoded Ambler Class D β-Lactamase ofShewanella oneidensisas a Progenitor of Carbapenem-Hydrolyzing Oxacillinase
Authors: Poirel Laurent , Héritier Claire , Nordmann Patrice 
Published: December 2003

ABSTRACTA chromosome-encoded β-lactamase gene from aShewanella oneidensisreference strain was cloned and expressed inEscherichia coli. It encoded a carbapenem-hydrolyzing Ambler class D β-lactamase, OXA-54, that shared 92% amino acid identity with the plasmid-encoded carbapenem-hydrolyzing oxacillinase OXA-48 fromKlebsiella pneumoniae. This work suggests thatShewanellaspp. may produce the progenitor of oxacillinases compromising the efficacy of imipenem in clinically relevant gram-negative pathogens.
In Vitro Activities of DA-7867, a Novel Oxazolidinone, against Recent Clinical Isolates of Aerobic and Anaerobic Bacteria
Authors: Yong Dongeun , Yum Jong Hwa , Lee Kyungwon , Chong Yunsop , Choi Sung Hak , Rhee Jae Keol 
Published: December 2003

ABSTRACT
In vitro activities of DA-7867, a novel oxazolidinone, were compared to those of linezolid and commonly used antimicrobials. DA-7867 had the lowest MIC for 90% of the aerobic gram-positive bacterial strains tested, ≤0.25 μg/ml, and it was more potent than linezolid.
Effects of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs on Biofilms and Planktonic Cells of
Candida albicans
Authors: Alem Mohammed A. S. , Douglas L. Julia 
Published: December 2003

ABSTRACT

Prostaglandins are now known to be produced by
Candida albicans
and may play an important role in fungal colonization. Their synthesis in mammalian cells is decreased by inhibitors of the cyclooxygenase isoenzymes required for prostaglandin formation. In the present study, a catheter disk model system was used to investigate the effects of nonsteroidal anti-inflammatory drugs (all cyclooxygenase inhibitors) on biofilm formation by three strains of
C. albicans.
Seven of nine drugs tested at a concentration of 1 mM inhibited biofilm formation. Aspirin, etodolac, and diclofenac produced the greatest effects, with aspirin causing up to 95% inhibition. Celecoxib, nimesulide, ibuprofen, and meloxicam also inhibited biofilm formation, but to a lesser extent. Aspirin was active against growing and fully mature (48-h) biofilms; its effect was dose related, and it produced significant inhibition (20 to 80%) at pharmacological concentrations. Simultaneous addition of prostaglandin E
2
abolished the inhibitory effect of 25 or 50 μM aspirin. At 1 mM, aspirin reduced the viability of biofilm organisms to 1.9% of that of controls. Surviving cells had a wrinkled appearance, as judged by scanning electron microscopy, and consisted of both yeasts and hyphae. Treatment with other cyclooxygenase inhibitors, such as etodolac, resulted in biofilms that consisted almost entirely of yeast cells. In conventional assays for germ tube formation, these drugs produced significant inhibition, whereas aspirin had little effect. Our findings suggest that cyclooxygenase-dependent synthesis of fungal prostaglandin(s) is important for both biofilm development and morphogenesis in
C. albicans
and may act as a regulator in these physiological processes. Our results also demonstrate that aspirin possesses potent antibiofilm activity in vitro and could be useful in combined therapy with conventional antifungal agents in the management of some biofilm-associated
Candida
infections.
Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia
Authors: Azoulay-Dupuis E. , Mohler J. , Bédos J. P. 
Published: December 2003

ABSTRACT

The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The
Streptococcus pneumoniae
isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 10
5
CFU (virulent strains) into immunocompetent mice or 10
7
CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of
S. pneumoniae
isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against
S. pneumoniae
, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.
Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant
Pseudomonas aeruginosa
Authors: Giamarellos-Bourboulis Evangelos J. , Adamis Theodoros , Laoutaris George , Sabracos Lambros , Koussoulas Vassilios , Mouktaroudi Maria , Perrea Despina , Karayannacos Panayotis E. , Giamarellou Helen 
Published: December 2003

ABSTRACT

Clarithromycin was administered intravenously to 55 rabbits to evaluate its effect on experimental sepsis caused by multidrug-resistant
Pseudomonas aeruginosa
. Acute pyelonephritis was induced after ligation of the right ureter and injection of 10
8
CFU of the test isolate per kg of body weight into the renal pelvis. The animals were divided into six groups: group A, controls; group B, rabbits that received one intravenous dose of 80 mg of clarithromycin per kg concomitantly with bacterial challenge; group C, rabbits that received two doses of clarithromycin, the second one of which was given 2 h after the first one; group D, rabbits that received 15 mg of amikacin per kg; group E, rabbits that received one dose of clarithromycin and amikacin; and group F, rabbits that received two doses of clarithromycin and amikacin. Serum endotoxin levels were estimated by the QCL-1000
Limulus
amoebocyte lysate assay, tumor necrosis factor alpha (TNF-α) levels were measured by a bioassay, and malondialdehyde (MDA) levels were measured by the thiobarbiturate assay. Viable bacterial counts in various tissue samples were also assessed. The mean survival times of the animals in groups A, B, C, D, E, and F were 4.50, 7.69, 4.07, 4.55, 11.55, and 11.60 days, respectively (
P
= 0.033 for group D versus group F,
P
= 0.006 for group D versus group E,
P
= not significant for group B versus group E,
P
= 0.042 for group C versus group F). Serum endotoxin levels were similar between groups at all sampling times; TNF-α and MDA levels in groups B, C, E, and F decreased significantly over follow-up. The numbers of viable bacterial cells in the infected kidney were similar among the groups; those in the liver, spleen, lungs, and mesenteral lymph nodes were significantly decreased in groups B, E, and F compared to those in groups A and D. It is concluded that a prolongation of survival in animals with experimental sepsis caused by multidrug-resistant
P. aeruginosa
was achieved after coadministration of clarithromycin and amikacin and that the increased survival was probably attributable to the immunomodulatory properties of clarithromycin.
Outcomes and Indications of Segmental Pancreatectomy
Authors: Shibata Satoshi , Sato Tsutomu , Andoh Hideaki , Yasui Ouki , Yoshioka Masato , Kurokawa Toshiaki , Watanabe Go , Ise Norihito , Kotanagi Hitoshi , Asanuma Yoshihiro , Koyama Kenji 
Published: December 2003

<i>Background/Aim:</i> To preserve pancreatic function, segmental pancreatectomy has been proposed for benign or low-malignancy tumors in the pancreatic body. Indications for the procedure, however, are still controversial. <i>Methods:</i> In this study, we investigated the advantages and disadvantages of segmental pancreatectomy compared with distal pancreatectomy and subsequently determined indications for segmental pancreatectomy. <i>Results:</i> The distal pancreatectomy patients had shorter operation times, lower incidence of operative complications, and shorter hospital stays compared to segmental pancreatectomy patients. Endocrine function in distal pancreatectomy patients deteriorated compared to that of segmental pancreatectomy patients. The postoperative 75-gram oral glucose tolerance test showed a diabetic pattern in 3 of 7 distal pancreatectomy patients, whereas none of the segmental pancreatectomy patients became diabetic after surgery. The relation between the length of the removed pancreas and plasma glucose at 2 h after the 75-gram glucose intake showed a significant correlation. <i>Conclusion:</i> According to our results, if the length of removed pancreas is longer than 12 cm, the patients will have a risk of acquiring diabetes. In those cases, the segmental pancreatectomy should be considered.
Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation
Authors: Kahn Joy , Byk Tamara , Jansson-Sjostrand Lottie , Petit Isabelle , Shivtiel Shoham , Nagler Arnon , Hardan Izhar , Deutsch Varda , Gazit Zulma , Gazit Dan , Karlsson Stefan , Lapidot Tsvee 
Published: December 2003

AbstractA major limitation to clinical stem cell–mediated gene therapy protocols is the low levels of engraftment by transduced progenitors. We report that CXCR4 overexpression on human CD34+ progenitors using a lentiviral gene transfer technique helped navigate these cells to the murine bone marrow and spleen in response to stromal-derived factor 1 (SDF-1) signaling. Cells overexpressing CXCR4 exhibited significant increases in SDF-1–mediated chemotaxis and actin polymerization compared with control cells. A major advantage of CXCR4 overexpression was demonstrated by the ability of transduced CD34+ cells to respond to lower, physiologic levels of SDF-1 when compared to control cells, leading to improved SDF-1–induced migration and proliferation/survival, and finally resulting in significantly higher levels of in vivo repopulation of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice including primitive CD34+/CD38-/low cells. Importantly, no cellular transformation was observed following transduction with the CXCR4 vector. Unexpectedly, we documented lack of receptor internalization in response to high levels of SDF-1, which can also contribute to increased migration and proliferation by the transduced CD34+ cells. Our results suggest CXCR4 overexpression for improved definitive human stem cell motility, retention, and multilineage repopulation, which could be beneficial for in vivo navigation and expansion of hematopoietic progenitors. (Blood. 2004;103:2942-2949)