bluuebunny/crossref_metadata_2025_split huggingface dataset:
Should Moxifloxacin Be Used for the Treatment of Extensively Drug-Resistant Tuberculosis? An Answer from a Murine Model
Authors: Poissy Julien , Aubry Alexandra , Fernandez Christine , Lott Marie-Catherine , Chauffour Aurelie , Jarlier Vincent , Farinotti Robert , Veziris Nicolas 
Published: August 2010

ABSTRACT

The prevalence of extensively drug-resistant tuberculosis (XDR-TB), defined as TB that is resistant to isoniazid, rifampin, fluoroquinolones, and aminoglycosides, is rising worldwide. The extent of
Mycobacterium tuberculosis
resistance to fluoroquinolones depends on the mutation in the DNA gyrase, the only target of fluoroquinolones. The MIC of moxifloxacin, the most active fluoroquinolone against
M. tuberculosis
, may be lower than its peak serum level for some ofloxacin-resistant strains of
Mycobacterium tuberculosis
. Therefore, if the MIC of moxifloxacin is lower than its peak serum level, it may be effective against XDR-TB. Our objective was to determine the efficacy of moxifloxacin in treating ofloxacin-resistant TB. We selected isogenic fluoroquinolone-resistant mutants of
M. tuberculosis
H37Rv
in vivo
. We infected Swiss mice with either wild-type H37Rv or one of three mutant strains with different MICs that are commonly seen in clinical practice. The MICs of the mutant strains ranged from below to above the peak moxifloxacin level seen in humans (3 μg/ml). Each mouse was treated with one of four moxifloxacin doses for 1 month. Moxifloxacin was effective against mutant strain GyrB D500N, with the lowest MIC (0.5 μg/ml), when the standard dose was doubled. Moxifloxacin reduced mortality in mice infected with mutant strain GyrA A90V with an intermediate MIC (2 μg/ml). However, it had no impact on the mutant strain GyrA D94G with the highest MIC (4 μg/ml). Our study underscores current WHO recommendations to use moxifloxacin when there is resistance to early-generation fluoroquinolones such as ofloxacin, restricting this recommendation to strains with moxifloxacin MICs of less than or equal to 2 μg/ml.
Reduced Expression of the
vca0421
Gene of
Vibrio cholerae
O1 Results in Innate Resistance to Ciprofloxacin
Authors: Okuda Jun , Hayashi Naoki , Wakahara Yuka , Gotoh Naomasa 
Published: August 2010

ABSTRACT

A mini-Tn
5
insertion into a ciprofloxacin (CIP)-resistant mutant of
Vibrio cholerae
O1 revealed that overexpression of the
vca0421
gene, which encodes a hypothetical protein, in the CIP-resistant mutant carrying a mutation in the quinolone resistance-determining region (QRDR) of the
gyrA
gene causes sensitization to CIP. We propose a new intrinsic mechanism of resistance to fluoroquinolones due to the inherently reduced expression of the
vca0421
gene in
V. cholerae
O1.
Translocation of
Pseudomonas aeruginosa
from the Intestinal Tract Is Mediated by the Binding of ExoS to an Na,K-ATPase Regulator, FXYD3
Authors: Okuda Jun , Hayashi Naoki , Okamoto Masashi , Sawada Shinji , Minagawa Shu , Yano Yoshitaka , Gotoh Naomasa 
Published: August 2010

ABSTRACT

The intestinal tract is considered the most important reservoir of
Pseudomonas aeruginosa
in intensive care units (ICUs). Gut colonization by
P. aeruginosa
underlies the development of invasive infections such as gut-derived sepsis. Intestinal colonization by
P. aeruginosa
is associated with higher ICU mortality rates. The translocation of endogenous
P. aeruginosa
from the colonized intestinal tract is an important pathogenic phenomenon. Here we identify bacterial and host proteins associated with bacterial penetration through the intestinal epithelial barrier. We first show by comparative genomic hybridization analysis that the
exoS
gene, encoding the type III effector protein, ExoS, was specifically detected in a clinical isolate that showed higher virulence in silkworms following midgut injection. We further show using a silkworm oral infection model that
exoS
is required both for virulence and for bacterial translocation from the midgut to the hemolymph. Using a bacterial two-hybrid screen, we show that the mammalian factor FXYD3, which colocalizes with and regulates the function of Na,K-ATPase, directly binds ExoS. A pulldown assay revealed that ExoS binds to the transmembrane domain of FXYD3, which also interacts with Na,K-ATPase. Na,K-ATPase controls the structure and barrier function of tight junctions in epithelial cells. Collectively, our results suggest that ExoS facilitates
P. aeruginosa
penetration through the intestinal epithelial barrier by binding to FXYD3 and thereby impairing the defense function of tight junctions against bacterial penetration.
Role of
Porphyromonas gingivalis
Phosphoserine Phosphatase Enzyme SerB in Inflammation, Immune Response, and Induction of Alveolar Bone Resorption in Rats
Authors: Bainbridge Brian , Verma Raj K. , Eastman Christie , Yehia Bilal , Rivera Mercedes , Moffatt Catherine , Bhattacharyya Indraneel , Lamont Richard J. , Kesavalu Lakshmyya 
Published: August 2010

ABSTRACT

Porphyromonas gingivalis
secretes a serine phosphatase enzyme, SerB, upon contact with gingival epithelial cells
in vitro
. The SerB protein plays a critical role in internalization and survival of the organism in epithelial cells. SerB is also responsible for the inhibition of interleukin-8 (IL-8) secretion from gingival epithelial cells infected with
P. gingivalis
. This study examined the ability of a
P. gingivalis
SerB mutant to colonize the oral cavity and induce gingival inflammation, immune responses, and alveolar bone resorption in a rat model of periodontal disease. Both
P. gingivalis
ATCC 33277 and an isogenic ΔSerB mutant colonized the oral cavities of rats during the 12-week experimental period. Both of the strains induced significant (
P
< 0.05) systemic levels of immunoglobulin G (IgG) and isotypes IgG1, IgG2a, and IgG2b, indicating the involvement of both T helper type 1 (Th1) and Th2 responses to infection. Both strains induced significantly (
P
< 0.05) higher levels of alveolar bone resorption in infected rats than in sham-infected control rats. However, horizontal and interproximal alveolar bone resorption induced by the SerB mutant was significantly (
P
< 0.05) lower than that induced by the parental strain. Rats infected with the ΔSerB mutant exhibited significantly higher levels of apical migration of the junctional epithelium (
P
< 0.01) and polymorphonuclear neutrophil (PMN) recruitment (
P
< 0.001) into the gingival tissues than rats infected with the wild type. In conclusion, in a rat model of periodontal disease, the SerB phosphatase of
P. gingivalis
is required for maximal alveolar bone resorption, and in the absence of SerB, more PMNs are recruited into the gingival tissues.
Adhesion, Invasion, and Agglutination Mediated by Two Trimeric Autotransporters in the Human Uropathogen
Proteus mirabilis
Authors: Alamuri Praveen , Löwer Martin , Hiss Jan A. , Himpsl Stephanie D. , Schneider Gisbert , Mobley Harry L. T. 
Published: August 2010

ABSTRACT

Fimbriae of the human uropathogen
Proteus mirabilis
are the only characterized surface proteins that contribute to its virulence by mediating adhesion and invasion of the uroepithelia. PMI2122 (AipA) and PMI2575 (TaaP) are annotated in the genome of strain HI4320 as trimeric autotransporters with “adhesin-like” and “agglutinating adhesin-like” properties, respectively. The C-terminal 62 amino acids (aa) in AipA and 76 aa in TaaP are homologous to the translocator domains of YadA from
Yersinia enterocolitica
and Hia from
Haemophilus influenzae
. Comparative protein modeling using the Hia three-dimensional structure as a template predicted that each of these domains would contain four antiparallel beta sheets and that they formed homotrimers. Recombinant AipA and TaaP were seen as ∼28 kDa and ∼78 kDa, respectively, in
Escherichia coli
, and each also formed high-molecular-weight homotrimers, thus supporting this model.
E. coli
synthesizing AipA or TaaP bound to extracellular matrix proteins with a 10- to 60-fold-higher level of affinity than the control strain. Inactivation of
aipA
in
P. mirabilis
strains significantly (
P
< 0.01) reduced the mutants' ability to adhere to or invade HEK293 cell monolayers, and the functions were restored upon complementation. A 51-aa-long invasin region in the AipA passenger domain was required for this function.
E. coli
expressing TaaP mediated autoagglutination, and a
taaP
mutant of
P. mirabilis
showed significantly (
P
< 0.05) more reduced aggregation than HI4320. Gly-247 in AipA and Gly-708 in TaaP were indispensable for trimerization and activity. AipA and TaaP individually offered advantages to
P. mirabilis
in a murine model. This is the first report characterizing trimeric autotransporters in
P. mirabilis
as afimbrial surface adhesins and autoagglutinins.
Socioeconomic impact of road traffic injuries in West Africa: exploratory data from Nigeria
Authors: Juillard Catherine , Labinjo Mariam , Kobusingye Olive , Hyder Adnan A 
Published: August 2010

BackgroundRoad traffic injuries (RTIs) are increasingly contributing to the burden of disease in sub-Saharan Africa, yet little is known about the economic consequences and disability associated with them.ObjectiveTo explore cost and disability consequences of RTIs in Nigeria.DesignA population-based survey using two-stage stratified cluster sampling.Subject/settingInformation on care-seeking choice, cost of treatment, ability to work, reduction in earnings, and disability were collected on 127 subjects who had suffered an RTI, of 3082 study subjects in seven Nigerian states.Outcome measuresUnivariate analysis was used to estimate frequency of disability, types of care sought, and trends for work lost, functional ability and cost of treatment. Unadjusted bivariate analysis was performed to explore care-seeking, cost of care, and work lost among disabled and non-disabled people.ResultsRTIs resulted in disability for 29.1% of subjects, while 13.5% were unable to return to work. Of the disabled people, 67.6% were unable to perform activities of daily living, 16.7% consequently lost their jobs, and 88.6% had a reduction in earnings. Private physician and hospital treatment were the most common forms of initial treatment sought, but traditional treatment was the most common second form of care sought. Average direct costs of informal and formal treatment were US$6.65 and US$35.64, respectively. Disabled people were more likely to seek formal care (p=0.003) and be unable to work (p=0.002).ConclusionsEconomic and functional ramifications must be included in the spectrum of consequences of RTIs to fully appreciate the extent of the burden of disease, implying that health systems should not only address the clinical consequences of RTIs, but the financial ones as well.
Decline in hospitalisations due to dog bite injuries in Catalonia, 1997–2008. An effect of government regulation?
Authors: Villalbí Joan R , Cleries Montse , Bouis Susana , Peracho Víctor , Duran Julia , Casas Conrad 
Published: August 2010

ObjectiveTo analyse population-based data on hospitalisation caused by dog bite injuries after changes in legal regulations on dog ownership, including breed-specific regulations.DesignDescriptive study.SettingHospitals in Catalonia (Spain), 1997–2008.SubjectsPersons hospitalised with injuries caused by dog bites.ResultsThere has been a significant decline in hospitalisation caused by injuries from dog bites from 1.80/100 000 in 1997–9 to 1.11/100 000 in 2006–8, after the enactment of stricter regulations on dog ownership in 1999 and 2002. The magnitude of this change is significant (−38%), and has been greatest in less urban settings.ConclusionsGovernment regulations were associated with a sizable decrease in injuries caused by dog bites in Catalonia. More evaluative studies in this field may provide criteria to focus future regulations and other preventive interventions.
Model driven code generation for critical and adaptative embedded systems
Authors: Borde Etienne , Feiler Peter H. , Haïk Grégory , Pautet Laurent 
Published: August 2010

Implementing adaptative systems requires to make the trade off of (i) the adaptation promptness, (ii) the amount of interferences due to adaptation, and (iii) the guarantee of data ows consistency. Furthermore, implementing critical systems requires to respect design constraints that enable to improve its determinism.
In this paper, we propose a design methodology that helps to make the adaptation trade off while respecting the critical systems design specificities. We then illustrate the usage of this methodology on an industrial use-case, using a component-based framework that generates the adaptation code. Lastly, we present and discuss the associated experimental results, and show the relative benefits of using the one or the other mode switch protocol.
microRNA Signature and Expression of Dicer and Drosha Can Predict Prognosis and Delineate Risk Groups in Neuroblastoma
Authors: Lin Ruey-Jen , Lin You-Chin , Chen Jeremy , Kuo Huan-Hsien , Chen Yuan-Yan , Diccianni Mitchell B. , London Wendy B. , Chang Chih-Hao , Yu Alice L. 
Published: August 2010

Abstract
Neuroblastoma is a common childhood tumor and accounts for 15% of pediatric cancer deaths. To investigate the microRNA (miRNA) profile and role of Dicer and Drosha in neuroblastoma, we assessed the expression of 162 human miRNAs, Dicer and Drosha in 66 neuroblastoma tumors by using real-time PCR methods. We found global downregulation of miRNA expression in advanced neuroblastoma and identified 27 miRNAs that can clearly distinguish low- from high-risk patients. Furthermore, expression levels of Dicer or Drosha were low in high-risk neuroblastoma tumors, which accounted for global downregulation of miRNAs in advanced disease and correlated with poor outcome. Notably, for patients with non–MYCN-amplified tumors, low expression of Dicer can serve as a significant and independent predictor of poor outcome (hazard ratio, 9.6; P = 0.045; n = 52). Using plausible neural networks to select a combination of 15 biomarkers that consist of 12 miRNAs' signature, expression levels of Dicer and Drosha, and age at diagnosis, we were able to segregate all patients into four distinct patterns that were highly predictive of clinical outcome. In vitro studies also showed that knockdown of either Dicer or Drosha promoted the growth of neuroblastoma cell lines. Our results reveal that a combination of 15 biomarkers can delineate risk groups of neuroblastoma and serve as a powerful predictor of clinical outcome. Moreover, our findings of growth promotion by silencing Dicer/Drosha implied their potential use as therapeutic targets for neuroblastoma. Cancer Res; 70(20); 7841–50. ©2010 AACR.
Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
Authors: Baselga José , Cervantes Andres , Martinelli Erika , Chirivella Isabel , Hoekman Klaas , Hurwitz Herbert I. , Jodrell Duncan I. , Hamberg Paul , Casado Esther , Elvin Paul , Swaisland Alan , Iacona Renee , Tabernero Josep 
Published: August 2010

Abstract
Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors.
Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing.
Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours.
Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.
Engineered Thio-Trastuzumab-DM1 Conjugate with an Improved Therapeutic Index to Target Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Authors: Junutula Jagath R. , Flagella Kelly M. , Graham Richard A. , Parsons Kathryn L. , Ha Edward , Raab Helga , Bhakta Sunil , Nguyen Trung , Dugger Debra L. , Li Guangmin , Mai Elaine , Lewis Phillips Gail D. , Hiraragi Hajime , Fuji Reina N. , Tibbitts Jay , Vandlen Richard , Spencer Susan D. , Scheller Richard H. , Polakis Paul , Sliwkowski Mark X. 
Published: August 2010

Abstract
Purpose: Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.
Experimental Design and Results: To generate thioTMAb-mpeo-DM1, one drug maytansinoid 1 (DM1) molecule was conjugated to an engineered cysteine residue at Ala114 (Kabat numbering) on each trastuzumab-heavy chain, resulting in two DM1 molecules per antibody. ThioTMAb-mpeo-DM1 retained similar in vitro anti–cell proliferation activity and human epidermal growth factor receptor 2 (HER2) binding properties to that of the conventional ADC. Furthermore, it showed improved efficacy over the conventional ADC at DM1-equivalent doses (μg/m2) and retained efficacy at equivalent antibody doses (mg/kg). An improved safety profile of &gt;2-fold was observed in a short-term target-independent rat safety study. In cynomolgus monkey safety studies, thioTMAb-mpeo-DM1 was tolerated at higher antibody doses (up to 48 mg/kg or 6,000 μg DM1/m2) compared with the conventional ADC that had dose-limiting toxicity at 30 mg/kg (6,000 μg DM1/m2).
Conclusions: The engineered thioTMAb-mpeo-DM1 with broadened therapeutic index represents a promising antibody drug conjugate for future clinical development of HER2-positive targeted breast cancer therapies. Clin Cancer Res; 16(19); 4769–78. ©2010 AACR.
Evaluation of AR-H067637, the active metabolite of the new direct thrombin inhibitor AZD0837, in models of venous and arterial thrombosis and bleeding in anaesthetised rats
Authors: Pehrsson Susanne , Johansson Karin , Kjaer Magnus , Elg Margareta 
Published: August 2010

SummaryAZD0837, currently in clinical development, is a once-daily oral anticoagulant that is bioconverted to AR-H067637, a selective, reversible direct thrombin inhibitor (DTI). When developing a new DTI, the anti-thrombotic effects are commonly investigated in in vivo animal models; this report shows the effect of AR-H067637 in venous and arterial thrombosis and bleeding models in anaesthetised rats. Thrombus formation was induced by topical application of ferric chloride to the carotid artery or to the caval vein with partial stasis. Cutaneous incision bleeding time and muscle transection blood loss were assessed, with or without acetylsalicylic acid (ASA). Activated partial thromboplastin time (APTT), ecarin coagulation time (ECT) and thrombin coagulation time (TCT) were used as plasma biomarkers of anticoagulant effect. Dalteparin was used as a reference compound. AR-H067637, given by continuous infusion, displayed a dose-dependent antithrombotic effect, with 50% inhibition (IC50) of thrombus size in venous and arterial thrombosis models obtained at plasma concentrations of 0.13 μM and 0.55 μM, respectively, without increased bleeding. Dose-dependent increased bleeding and blood loss were seen at plasma concentrations ≥1 μM AR-H067637. At the highest AR-H067637 plasma concentration tested, bleeding time and blood loss increased two and four times the vehicle group. Addition of ASA moderately potentiated bleeding time and blood loss. APTT, ECT and TCT were dose-dependently prolonged. These studies demonstrate that the DTI AR-H067637 inhibits thrombus formation in rat venous and arterial thrombosis models with no or minor increases in bleeding.
C1 inhibitor, a multi-functional serine protease inhibitor
Authors: Lu Fengxin , Mejia Pedro , Davis Alvin 
Published: August 2010

SummaryC1 inhibitor (C1INH) is a serpin that regulates both complement and contact (kallikrein-kinin) system activation. It consists of a serpin domain that is highly homologous to other serpins and an amino terminal non-serpin mucin-like domain. Deficiency of C1INH results in hereditary angioedema, a disease characterised by episodes of angioedema of the skin or the mucosa of the gastrointestinal tract or the oropharynx. Although early data suggested that angioedema was mediated via complement system activation, the preponderance of the data indicate that bradykinin is the mediator. In the past few years, it has become apparent that C1INH has additional anti-inflammatory functions independent of protease inhibition. These include interactions with leukocytes that may result in enhanced phagocytosis, with endothelial cells via Eand P-selectins that interfere with leukocyte rolling and in turn results in suppression of transmigration of leukocytes across the endothelium, and interactions with extracellular matrix components that may serve to concentrate C1INH at sites of inflammation. In addition, C1INH suppresses gram negative sepsis and endotoxin shock, partly via direct interaction with endotoxin that interferes with its interaction with macrophages, thereby suppressing tumour necrosis factor-α and other inflammatory mediators. C1INH treatment improves outcome in a number of disease models, including sepsis and other bacterial infections, possibly malaria, ischaemia-reperfusion injury (intestinal, hepatic, muscle, cardiac, brain), hyper-acute transplant rejection, and other inflammatory disease models. Recent data suggest that this effectiveness is the result of mechanisms that do not require protease inhibition, in addition to both complement and contact system activation.