bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Nonazole CYP51 Inhibitor Cures Chagas’ Disease in a Mouse Model of Acute Infection
Authors: Doyle Patricia S. , Chen Chiung-Kuang , Johnston Jonathan B. , Hopkins Stephanie D. , Leung Siegfried S. F. , Jacobson Matthew P. , Engel Juan C. , McKerrow James H. , Podust Larissa M. 
Published: April 2010

ABSTRACT

Chagas’ disease, the leading cause of heart failure in Latin America, is caused by the kinetoplastid protozoan
Trypanosoma cruzi.
The sterols of
T. cruzi
resemble those of fungi, both in composition and in biosynthesis. Azole inhibitors of sterol 14α-demethylase (CYP51) successfully treat fungal infections in humans, and efforts to adapt the success of antifungal azoles posaconazole and ravuconazole as second-use agents for Chagas’ disease are under way. However, to address concerns about the use of azoles for Chagas’ disease, including drug resistance and cost, the rational design of nonazole CYP51 inhibitors can provide promising alternative drug chemotypes. We report the curative effect of the nonazole CYP51 inhibitor LP10 in an acute mouse model of
T. cruzi
infection. Mice treated with an oral dose of 40 mg LP10/kg of body weight twice a day (BID) for 30 days, initiated 24 h postinfection, showed no signs of acute disease and had histologically normal tissues after 6 months. A very stringent test of cure showed that 4/5 mice had negative PCR results for
T. cruzi
, and parasites were amplified by hemoculture in only two treated mice. These results compare favorably with those reported for posaconazole. Electron microscopy and gas chromatography-mass spectrometry (GC-MS) analysis of sterol composition confirmed that treatment with LP10 blocked the 14α-demethylation step and induced breakdown of parasite cell membranes, culminating in severe ultrastructural and morphological alterations and death of the clinically relevant amastigote stage of the parasite.
In Vitro
Activity of Telavancin against a Contemporary Worldwide Collection of
Staphylococcus aureus
Isolates
Authors: Mendes Rodrigo E. , Moet Gary J. , Janechek Mike J. , Jones Ronald N. 
Published: April 2010

ABSTRACT

The activity of telavancin and comparators was assessed against a contemporary (2007 and 2008) global collection of 10,000 isolates of
Staphylococcus aureus
. Telavancin was very active against methicillin-susceptible and -resistant
S
.
aureus
(MSSA and MRSA, respectively; MIC
50/90
for both, 0.12/0.25 μg/ml; 100.0% susceptible). This agent was 2-, 4-, and 8-fold more potent than daptomycin (MIC
90
, 0.5 μg/ml), vancomycin or quinupristin-dalfopristin (MIC
90
, 1 μg/ml), and linezolid (MIC
90
, 2 μg/ml) against MRSA, respectively. These data show a potent activity of telavancin tested against a current global collection of
S
.
aureus
.
Intra- and Interlaboratory Performances of Two Commercial Antimicrobial Susceptibility Testing Methods for Bifidobacteria and Nonenterococcal Lactic Acid Bacteria
Authors: Huys Geert , D'Haene Klaas , Cnockaert Margo , Tosi Lorenzo , Danielsen Morten , Flórez Ana Belén , Mättö Jaana , Axelsson Lars , Korhonen Jenni , Mayrhofer Sigrid , Egervärn Maria , Giacomini Mauro , Vandamme Peter 
Published: April 2010

ABSTRACT

In a small-scale harmonization study involving nine laboratories in eight European countries, the intra- and interlaboratory performances of two commercially available systems, i.e., the VetMIC microplate system and Etest, for antimicrobial susceptibility testing of nonenterococcal lactic acid bacteria (NELAB) and bifidobacteria were analyzed. In addition, one laboratory also performed standard broth microdilution as a reference method. MICs of tetracycline, erythromycin, ampicillin, gentamicin, clindamycin, and streptomycin for the type strains of 25 species of NELAB and bifidobacteria and MICs of vancomycin for a selection of relevant taxa were determined. The previously described lactic acid bacterium susceptibility test medium (LSM) and related mixed-medium formulations, all including Iso-Sensitest broth as a basic component, were used as test media. The overall agreement of median MIC ranges ± 1 log
2
dilution determined by the VetMIC and Etest methods with the median MICs determined by the reference method was very good for tetracycline, ampicillin, and streptomycin (92.3 to 100%) but low for erythromycin (19.5 to 30.7%) and clindamycin (50.0 to 80.8%). There was a consensus among the participating laboratories that VetMIC was preferred over Etest because of its lower cost, better growth support, and more uniform criteria for MIC end point reading. With the range for acceptable intralaboratory reproducibility being defined as the median MIC ± 1 log
2
dilution, VetMIC results (with 69.2% of all data sets in the acceptable range) were shown to display greater reproducibility than Etest results (with 58.8% of all data sets in the acceptable range). Also at the interlaboratory level, the proportion of MIC values obtained with VetMIC that belonged to the complete agreement category (60.0%) was higher than the proportion of such values obtained with Etest (47.0%), which indicates a higher degree of interlaboratory reproducibility for the former method. Apart from some agent-specific effects, the majority of VetMIC and Etest replicate data sets were situated within a 1- to 2-log
2
dilution range, suggesting that the two methods can be considered to be equivalent for recognizing resistance phenotypes. This multicenter study has further validated the standard use of LSM and related mixed-medium formulations with commercially available systems and formed the basis for the ongoing development of the ISO 10932/IDF 223 standard for susceptibility testing of NELAB and bifidobacteria.
Azole Resistance Profile of Amino Acid Changes in
Aspergillus fumigatus
CYP51A Based on Protein Homology Modeling
Authors: Snelders Eveline , Karawajczyk Anna , Schaftenaar Gijs , Verweij Paul E. , Melchers Willem J. G. 
Published: April 2010

ABSTRACT

Molecular studies have shown that the majority of azole resistance in
Aspergillus fumigatus
is associated with amino acid substitutions in the
cyp51A
gene. To obtain insight into azole resistance mutations, the
cyp51A
gene of 130 resistant and 76 susceptible
A. fumigatus
isolates was sequenced. Out of 130 azole-resistant isolates, 105 contained a tandem repeat of 34 bp in the promoter region and a leucine-to-histidine substitution in codon 98 (designated TR/L98H). Additionally, in 12 of these TR/L98H resistant isolates, the mutations S297T and F495I were found, and in 1 isolate, the mutation F495I was found. In eight azole-resistant isolates, known azole resistance mutations were detected in codon G54, G138, or M220. In three azole-susceptible isolates, the mutation E130D, L252L, or S400I was found and in 13 azole-susceptible isolates but also in 1 azole-resistant isolate, the mutations F46Y, G98G, M172V, N248T, D255E, L358L, E427K, and C454C were found. All of the nonsynonymous mutations, apart from the mutations in codons G54, G138, and M220 and L98H, were located at the periphery of the protein, as determined by a structural model of the
A. fumigatus
Cyp51A protein, and were predicted neither to interact with azole compounds nor to affect structural integrity. Therefore, this wide diversity of mutations in the
cyp51A
gene in azole-susceptible
A. fumigatus
isolates is not correlated with azole resistance. Based on the Cyp51A protein homology model, the potential correlation of a mutation to azole resistance can be predicted.
In Vitro
Interactions between New Antitubercular Drug Candidates SQ109 and TMC207
Authors: Reddy Venkata M. , Einck Leo , Andries K. , Nacy Carol A. 
Published: April 2010

ABSTRACT

The
in vitro
interactions of two new antitubercular drugs, SQ109 and TMC207, with each other and with rifampin (RIF) were evaluated. The combination of SQ109 with TMC207 (i) improved an already excellent TMC207 MIC for
M. tuberculosis
H37Rv by 4- to 8-fold, (ii) improved the rate of killing of bacteria over the rate of killing by each single drug, and (iii) enhanced the drug postantibiotic effect by 4 h. In no instance did we observe antagonistic activities with the combination of SQ109 and TMC207. Rifampin activates cytochrome P450 genes to reduce the area under the curve (AUC) for TMC207 in humans. The presence of RIF in three-drug combinations did not affect the synergistic activities of SQ109 and TMC207, and SQ109 also dramatically decreased the MIC of RIF. SQ109 was active by itself, and both its activity was improved by and it improved the
in vitro
activities of both RIF and TMC207.
OXA-24 Carbapenemase Gene Flanked by XerC/XerD-Like Recombination Sites in Different Plasmids from Different
Acinetobacter
Species Isolated during a Nosocomial Outbreak
Authors: Merino María , Acosta Joshi , Poza Margarita , Sanz Francisca , Beceiro Alejandro , Chaves Fernando , Bou Germán 
Published: April 2010

ABSTRACT

A clinical strain of
Acinetobacter calcoaceticus
resistant to carbapenems was isolated from a blood culture sample from an inpatient in a hospital in Madrid (Spain) during a large outbreak of infection (affecting more than 300 inpatients), caused by a multidrug-resistant
Acinetobacter baumannii
clone. The carbapenem resistance in both the
A. calcoaceticus
and
A. baumannii
clones was due to a
bla
OXA-24
gene harbored in different plasmids. The plasmids were fully sequenced, revealing the presence of site-specific recombination binding sites putatively involved in mobilization of the
bla
OXA-24
gene. Comparison of plasmids contained in the two strains revealed possible horizontal transmission of resistance genes between the
Acinetobacter
species.
Antimicrobial Activity of a Halocidin-Derived Peptide Resistant to Attacks by Proteases
Authors: Shin Yong Pyo , Park Ho Jin , Shin Seo Hwa , Lee Young Shin , Park Seungmi , Jo Sungho , Lee Yong Ho , Lee In Hee 
Published: April 2010

ABSTRACT

Cationic antimicrobial peptides (AMPs) have attracted a great deal of interest as a promising candidate for a novel class of antibiotics that might effectively treat recalcitrant infections caused by a variety of microbes that are resistant to currently available drugs. However, the AMPs are inherently limited in that they are inevitably susceptible to attacks by proteases generated by human and pathogenic microbes; this vulnerability severely hinders their pharmaceutical use in human therapeutic protocols. In this study, we report that a halocidin-derived AMP, designated HG1, was found to be resistant to proteolytic degradation. As a result of its unique structural features, HG1 proved capable of preserving its antimicrobial activity after incubation with trypsin, chymotrypsin, and human matrix metalloprotease 7 (MMP-7). Additionally, HG1 was observed to exhibit profound antimicrobial activity in the presence of fluid from human skin wounds or proteins extracted from the culture supernatants of
Staphylococcus aureus
and
Pseudomonas aeruginosa
. Greater understanding of the structural motifs of HG1 required for its protease resistance might provide feasible ways to solve the problems intrinsic to the development of an AMP-based antibiotic.
Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo
Authors: Horzempa Joseph , O'Dee Dawn M. , Shanks Robert M. Q. , Nau Gerard J. 
Published: April 2010

ABSTRACTThe pathogenesis ofFrancisella tularensishas been associated with this bacterium's ability to replicate within macrophages.F. tularensiscan also invade and replicate in a variety of nonphagocytic host cells, including lung and kidney epithelial cells and hepatocytes. As uracil biosynthesis is a central metabolic pathway usually necessary for pathogens, we characterized ΔpyrFmutants of bothF. tularensisLVS and Schu S4 to investigate the role of these mutants in intracellular growth. As expected, these mutant strains were deficient inde novopyrimidine biosynthesis and were resistant to 5-fluoroorotic acid, which is converted to a toxic product by functional PyrF. TheF. tularensisΔpyrFmutants could not replicate in primary human macrophages. The inability to replicate in macrophages suggested that theF. tularensisΔpyrFstrains would be attenuated in animal infection models. Surprisingly, these mutants retained virulence during infection of chicken embryos and in the murine model of pneumonic tularemia. We hypothesized that theF. tularensisΔpyrFstrains may replicate in cells other than macrophages to account for their virulence. In support of this,F. tularensisΔpyrFmutants replicated in HEK-293 cells and normal human fibroblastsin vitro. Moreover, immunofluorescence microscopy showed abundant staining of wild-type and mutant bacteria in nonmacrophage cells in the lungs of infected mice. These findings indicate that replication in nonmacrophages contributes to the pathogenesis ofF. tularensis.
Lactobacillus jensenii
Surface-Associated Proteins Inhibit
Neisseria gonorrhoeae
Adherence to Epithelial Cells
Authors: Spurbeck Rachel R. , Arvidson Cindy Grove 
Published: April 2010

ABSTRACT

High numbers of lactobacilli in the vaginal tract have been correlated with a decreased risk of infection by the sexually transmitted pathogen
Neisseria gonorrhoeae
. We have previously shown that
Lactobacillus jensenii
, one of the most prevalent microorganisms in the healthy human vaginal tract, can inhibit gonococcal adherence to epithelial cells in culture. Here we examined the role of the epithelial cells and the components of
L. jensenii
involved in the inhibition of gonococcal adherence.
L. jensenii
inhibited the adherence of gonococci to glutaraldehyde-fixed epithelial cells like it inhibited the adherence of gonococci to live epithelial cells, suggesting that the epithelial cells do not need to be metabolically active for the inhibition to occur. In addition, methanol-fixed
L. jensenii
inhibited gonococcal adherence to live epithelial cells, indicating that
L. jensenii
uses a constitutive component to inhibit gonococcal interactions with epithelial cells. Proteinase K treatment of methanol-fixed lactobacilli eliminated the inhibitory effect, suggesting that the inhibitory component contains protein. Released surface components (RSC) isolated from
L. jensenii
were found to contain at least two inhibitory components, both of which are protease sensitive. Using anion-exchange and size exclusion chromatography, an inhibitory protein which exhibits significant similarity to the enzyme enolase was isolated. A recombinant His
6
-tagged version of this protein was subsequently produced and shown to inhibit gonococcal adherence to epithelial cells in a dose-dependent manner.
Rickettsia rickettsiiInfection of Human Macrovascular and Microvascular Endothelial Cells Reveals Activation of Both Common and Cell Type-Specific Host Response Mechanisms
Authors: Rydkina Elena , Turpin Loel C. , Sahni Sanjeev K. 
Published: April 2010

ABSTRACTAlthough inflammation and altered barrier functions of the vasculature, due predominantly to the infection of endothelial cell lining of small and medium-sized blood vessels, represent salient pathological features of human rickettsioses, the interactions between pathogenic rickettsiae and microvascular endothelial cells remain poorly understood. We have investigated the activation of nuclear transcription factor-kappa B (NF-κB) and p38 mitogen-activated protein (MAP) kinase, expression of heme oxygenase 1 (HO-1) and cyclooxygenase 2 (COX-2), and secretion of chemokines and prostaglandins afterRickettsia rickettsiiinfection of human cerebral, dermal, and pulmonary microvascular endothelial cells in comparison with pulmonary artery cells of macrovascular origin. NF-κB and p38 kinase activation and increased HO-1 mRNA expression were clearly evident in all cell types, along with relatively similar susceptibility toR. rickettsiiinfectionin vitrobut considerable variations in the intensities/kinetics of the aforementioned host responses. As expected, the overall activation profiles of macrovascular endothelial cells derived from human pulmonary artery and umbilical vein were nearly identical. Interestingly, cerebral endothelial cells displayed a marked refractoriness in chemokine production and secretion, while all other cell types secreted various levels of interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) in response to infection. A unique feature of all microvascular endothelial cells was the lack of induced COX-2 expression and resultant inability to secrete prostaglandin E2afterR. rickettsiiinfection. Comparative evaluation thus yields the first experimental evidence for the activation of both common and unique cell type-specific host response mechanisms in macrovascular and microvascular endothelial cells infected withR. rickettsii, a prototypical species known to cause Rocky Mountain spotted fever in humans.
Reduced ADAMTS13 in children with severe meningococcal sepsis is associated with severity and outcome
Authors: Bongers Tamara , Emonts Marieke , de Maat Moniek , Groot Ronald de , Lisman Ton , Hazelzet Jan , Leebeek Frank 
Published: April 2010

SummaryMultiple organ failure is a common feature of pediatric meningococcal sepsis and is associated with an imbalance of coagulation and fibrinolysis. This is partly due to an increased secretion of prothrombotic ultra-large von Willebrand factor (VWF) as the result of vascular endothelial damage. Another factor that may contribute is ADAMTS13, which converts VWF into smaller, less active, VWF multimers and thus influences VWF activity in plasma. We investigated the role of ADAMTS13 and VWF in the severity and outcome of sepsis. In 58 children with severe meningococcal sepsis we measured ADAMTS13 activity and antigen, VWF collagen binding activity (VWF:CB) and antigen levels (VWF:Ag), VWF propeptide and factor VIII at different time points during their stay in the paediatric intensive care unit. In the acute phase, both ADAMTS13 activity and antigen were decreased (median 23.4% and 33.7% of normal, respectively) and VWF:CB and VWF:Ag levels were strongly increased (325% and 348%, respectively.) ADAMTS13 antigen (23.9% vs. 34.6%; p=0.06) and VWF:CB (240% and 340% p<0.001) were lower in non-survivors than in survivors. ADAMTS13 activity and VWF:CB were both correlated with the severity of the disease, as indicated by the Pediatric Risk of Mortality score (Rs= –0.38 and Rs= –0.50, p=0.01, respectively, p<0.001). In the acute phase of severe sepsis decreased levels of ADAMTS13 and increased levels of VWF are observed, and the changes are related to severity of disease and outcome. This may contribute to the formation of microthrombi and the severity of thrombotic sequelae of sepsis.
Oral administration of a microencapsulated low-molecular-weight heparin to rabbits: Anti-Xa and anti-IIa profiles
Authors: Javot Lucie , Sapin Anne , Scala-Bertola Julien , Vigneron Claude , Lecompte Thomas , Maincent Philippe 
Published: April 2010

SummaryThe development of heparin oral form has been a subject of international research for a long time. Promising results have been obtained in vivo in terms of anti-Xa activity with different strategies and notably microparticles but studies concerning the anti-IIa activity and the anti-Xa/anti-IIa ratio have never been presented. Anti-Xa activities, anti-IIa activities and anti-Xa/anti-IIa ratios provided by nadroparin Eudragit→ RS and poly (D,L-lactic-co-glycolic acid) (PLGA) microparticles were determined in vitro and in vivo and an evaluation of their pharmacokinetic parameters compared to subcutaneous injection was performed. Nadroparin was encapsulated into microparticles prepared by the double emulsion method using Eudragit→ RS alone or in mixture with PLGA of two kinds, i.e. with (PLGA S) or without (PLGA H) esterification of the acid ending. Microparticles characterisation was performed (size, anti-Xa and anti-IIa activities entrapped and released) before their oral administration in rabbits. In vitro anti-Xa/anti-IIa ratios released from nadroparin microparticles were higher than the ratio of the commercial solution. After oral administration, whatever the formulation, sustained anti-Xa and anti-IIa activities were obtained compared to the subcutaneous injection with a peak concentration at 4 hours (up to 0.59 anti-Xa U/ml and 0.11 anti-IIa U/ml for PLGA S 50% / ERS 50% formulation). Anti-Xa and anti-IIa relative bioavailabilities were high, up to 40% (ERS 100% formulation). Anti-Xa/anti-IIa ratios were within range already obtained for subcutaneous injection, i.e. between 5 and 15. Nadroparin microparticles of nadroparin are promising oral dosage form performing sustained and well controlled anti-Xa, anti-IIa activities and anti-Xa/anti-IIa ratio.
Serum albumin and risk of venous thromboembolism
Authors: Lutsey Pamela L. , Heckbert Susan R. , Cushman Mary , Folsom Aaron R. 
Published: April 2010

SummaryThe incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms
Authors: Tyner Jeffrey W. , Bumm Thomas G. , Deininger Jutta , Wood Lisa , Aichberger Karl J. , Loriaux Marc M. , Druker Brian J. , Burns Christopher J. , Fantino Emmanuelle , Deininger Michael W. 
Published: April 2010

Abstract
Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5μM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2V617F allele burden, JAK2V617F cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2V617F cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells.