bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Ciprofloxacin Exposure on Staphylococcus aureus Genomic Alterations Linked with Emergence of Rifampin Resistance
Authors: Didier Jean-Philippe , Villet Régis , Huggler Elzbieta , Lew Daniel P. , Hooper David C. , Kelley William L. , Vaudaux Pierre 
Published: March 2011

ABSTRACT

Intensive use of antimicrobial agents in health care settings not only leads to the selection of multiresistant nosocomial isolates of
Staphylococcus aureus
but may also promote endogenous, resistance-conferring mutations in bacterial genes that encode drug targets. We evaluated the spectrum of rifampin resistance-conferring mutations in cultures of methicillin-susceptible
S. aureus
(MSSA) or methicillin-resistant
S. aureus
(MRSA) strains exposed
in vitro
to sub-MICs of ciprofloxacin. Growth of ciprofloxacin-susceptible MRSA strain MRGR3 and ciprofloxacin-resistant MSSA strain RA1 (a NCTC 8325 derivative) in the presence of 1/2× or 1/4× MIC of ciprofloxacin led to higher frequencies of rifampin-resistant mutants on agar supplemented with rifampin (0.25 mg/liter) than under ciprofloxacin-free conditions. While rifampin-resistant mutants from ciprofloxacin-free cultures essentially showed single-amino-acid substitutions, a significant proportion of rifampin-resistant mutants from ciprofloxacin-exposed cultures displayed in-frame deletions or insertions in the
rpoB
gene at several positions of the rifampin resistance cluster I. In-frame deletions or insertions were also recorded in
rpoB
cluster I of rifampin-resistant mutants from ciprofloxacin-exposed cultures of
mutS
and
mutL
DNA repair mutants of ciprofloxacin-resistant
S. aureus
strain RA1. Frequencies of rifampin-resistant mutants grown under ciprofloxacin-free medium were higher for mutant strains RA1
mutS2
and RA1
mutL
, but not RA1
recA
, than for their parent RA1. In conclusion, ciprofloxacin-mediated DNA damage in
S. aureus
, as exemplified by the wide diversity of deletions or insertions in
rpoB
, suggests the occurrence of major, quinolone-mediated disturbances in DNA fork progression and replication repair. Besides promoting antibiotic resistance, accumulation of unrepaired DNA replication errors, including insertions and deletions, may also contribute to potentially lethal mutations.
Attributable Hospital Cost and Antifungal Treatment of Invasive Fungal Diseases in High-Risk Hematology Patients: an Economic Modeling Approach
Authors: Ananda-Rajah Michelle R. , Cheng Allen , Morrissey C. Orla , Spelman Tim , Dooley Michael , Neville A. Munro , Slavin Monica 
Published: March 2011

ABSTRACT

Studies using patient-level data to determine the attributable cost of invasive fungal diseases (IFDs) are few. Using a case-control study with activity-based costing of patients admitted to a quaternary hospital from 2002 to 2007, we determined attributable hospitalization cost (and 12 weeks thereafter), length of stay (LOS), and costly antifungal treatment (C-AT; liposomal amphotericin B, voriconazole, posaconazole, caspofungin), expressed as defined daily doses (DDDs) per IFD episode, in patients with hematological malignancies and hematopoietic stem cell recipients. Matching criteria and median regression modeling controlled for confounding variables, including LOS prior to IFD onset. Multiple mycoses were identified in 43 matched case-control pairs (
n
= 86). A separate sensitivity analysis included 22 unmatched patients. IFD status was associated with a median excess cost of AU$30,957 (95% confidence interval [CI] = AU$2,368 to AU$59,546;
P
= 0.034), approximating at purchasing power parity US$21,203 (95% CI = US$1,622 to US$40,784) and €15,788 (95% CI = €1,208 to €30,368), increasing to AU$80,291 (95% CI = AU$33,636 to AU$126,946;
P
= 0.001), i.e., US$54,993 (95% CI = US$23,038 to US$86,948) and €40,948 (95% CI = €17,154 to €64,742), with intensive care unit (ICU) requirement. Cost determinants were pharmacy costs (64%;
P
< 0.001) inclusive of antifungal treatment (27%;
P
< 0.001) and ward costs (27%;
P
= 0.091), with proportions persisting through 12 weeks for 25 surviving matched pairs (pharmacy, 60% [
P
= 0.12]; ward, 31% [
P
= 0.21]). Median LOS was not significantly increased unless unmatched patients were included (8 days, 95% CI = 1.8 to 14 days;
P
= 0.012). Excess C-ATs were 17 DDDs (95% CI = 15 to 19 DDDs;
P
< 0.001) per case patient and 19 DDDs (95% CI = 16 to 22 DDDs;
P
< 0.001) per ICU patient. The sensitivity analysis was confirmatory (for median cost, AU$29,441, 95% CI = AU$5,571 to AU$53,310,
P
= 0.016; for C-AT, 17 DDDs, 95% CI = 16 to 18 DDDs,
P
< 0.001). IFD results in increased hospital and ICU costs, with pharmacy costs, including antifungal treatment, being major determinants. Consumption of costly antifungal drugs may be a novel resource metric with wider generalizability than cost alone.
Emergence of Linezolid-Resistant Mutants in a Susceptible-Cell Population of Methicillin-Resistant Staphylococcus aureus
Authors: Ikeda-Dantsuji Yurika , Hanaki Hideaki , Nakae Taiji , Takesue Yoshio , Tomono Kazunori , Honda Junichi , Yanagihara Katsunori , Mikamo Hiroshige , Fukuchi Kunihiko , Kaku Mitsuo , Kohno Shigeru , Niki Yoshihito 
Published: March 2011

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
with a MIC of linezolid of 4 μg/ml, isolated from a patient who had undergone unsuccessful linezolid therapy, yielded linezolid-resistant mutants in blood agar at 48 h of incubation. The resistant clones showed a MIC of linezolid ranging from 8 to 64 μg/ml and accumulated the T2500A mutation(s) of the rRNA genes. Emergence of these resistant clones appears to be facilitated by a cryptic mutation or mutations associated with chloramphenicol resistance.
Selection and Characterization of HIV-1 with a Novel S68 Deletion in Reverse Transcriptase
Authors: Schinazi Raymond F. , Massud Ivana , Rapp Kimberly L. , Cristiano Meta , Detorio Mervi A. , Stanton Richard A. , Bennett Matthew A. , Kierlin-Duncan Monique , Lennerstrand Johan , Nettles James H. 
Published: March 2011

ABSTRACTResistance to human immunodeficiency virus type 1 (HIV-1) represents a significant problem in the design of novel therapeutics and the management of treatment regimens in infected persons. Resistance profiles can be elucidated by defining modifications to the viral genome conferred upon exposure to novel nucleoside reverse transcriptase (RT) inhibitors (NRTI).In vitrotesting of HIV-1LAI-infected primary human lymphocytes treated with β-d-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (DFC; Dexelvucitabine; Reverset) produced a novel deletion of AGT at codon 68 (S68Δ) alone and in combination with K65R that differentially affects drug response. Dual-approach clone techniques utilizing TOPO cloning and pyrosequencing confirmed the novel S68Δ in the HIV-1 genome. The S68Δ HIV-1 RT was phenotyped against various antiviral agents in a heteropolymeric DNA polymerase assay and in human lymphocytes. Drug susceptibility results indicate that the S68Δ displayed a 10- to 30-fold increase in resistance to DFC, lamivudine, emtricitabine, tenofovir, abacavir, and amdoxovir and modest resistance to stavudine, β-d-2′,3′-oxa-5-fluorocytidine, or 9-(β-d-1,3-dioxolan-4-yl)guanine and remained susceptible to 3′-azido-3′-deoxythymidine, 2′,3′-dideoxyinosine (ddI), 1-(β-d-dioxolane)thymine (DOT) and lopinavir. Modeling revealed a central role for S68 in affecting conformation of the β3-β4 finger region and provides a rational for the selective resistance. These data indicate that the novel S68Δ is a previously unrecognized deletion that may represent an important factor in NRTI multidrug resistance treatment strategies.
Activity of NXL104 in Combination with β-Lactams against Genetically Characterized Escherichia coli and Klebsiella pneumoniae Isolates Producing Class A Extended-Spectrum β-Lactamases and Class C β-Lactamases
Authors: Lagacé-Wiens P. R. S. , Tailor F. , Simner P. , DeCorby M. , Karlowsky J. A. , Walkty A. , Hoban D. J. , Zhanel G. G. 
Published: March 2011

ABSTRACT

The novel non-β-lactam β-lactamase inhibitor NXL104, in combination with cefepime, ceftazidime, ceftriaxone, amdinocillin, and meropenem, was tested against 190 extended-spectrum β-lactamase (ESBL)-producing
Escherichia coli
and
Klebsiella pneumoniae
isolates, 94 AmpC-hyperproducing
E. coli
isolates, and 8 AmpC/ESBL-coexpressing
E. coli
isolates. NXL104 restored 100% susceptibility to the partner cephalosporins for all isolates tested. Amdinocillin and meropenem MICs were modestly improved (2 to 32 times lower) by NXL104. These results suggest that NXL104 may be useful in combination with β-lactams for the treatment of infections caused by ESBL- and AmpC-producing
Enterobacteriaceae
.
Antigen-Specific CD8
+
T Cells Fail To Respond to Shigella flexneri
Authors: Jehl Stephanie P. , Doling Amy M. , Giddings Kara S. , Phalipon Armelle , Sansonetti Philippe J. , Goldberg Marcia B. , Starnbach Michael N. 
Published: March 2011

ABSTRACT

CD8
+
T lymphocytes often play a primary role in adaptive immunity to cytosolic microbial pathogens. Surprisingly, CD8
+
T cells are not required for protective immunity to the enteric pathogen
Shigella flexneri
, despite the ability of
Shigella
to actively secrete proteins into the host cytoplasm, a location from which antigenic peptides are processed for presentation to CD8
+
T cells. To determine why CD8
+
T cells fail to play a role in adaptive immunity to
S. flexneri
, we investigated whether antigen-specific CD8
+
T cells are primed during infection but are unable to confer protection or, alternatively, whether T cells fail to be primed. To test whether
Shigella
is capable of stimulating an antigen-specific CD8
+
T-cell response, we created an
S. flexneri
strain that constitutively secretes a viral CD8
+
T-cell epitope via the
Shigella
type III secretion system and characterized the CD8
+
T-cell response to this strain both in mice and in cultured cells. Surprisingly, no T cells specific for the viral epitope were stimulated in mice infected with this strain, and cells infected with the recombinant strain were not targeted by epitope-specific T cells. Additionally, we found that the usually robust T-cell response to antigens artificially introduced into the cytoplasm of cultured cells was significantly reduced when the antigen-presenting cell was infected with
Shigella
. Collectively, these results suggest that antigen-specific CD8
+
T cells are not primed during
S. flexneri
infection and, as a result, afford little protection to the host during primary or subsequent infection.
Identification of Cytokeratin 18 as a Biomarker of Mouse and Human Hepatosplenic Schistosomiasis
Authors: Manivannan Bhagyashree , Rawson Pisana , Jordan T. William , Karanja Diana M. S. , Mwinzi Pauline N. M. , Secor William Evan , La Flamme Anne Camille 
Published: March 2011

ABSTRACTPreviously, we demonstrated unique protein expression patterns in 20-week-Schistosoma mansoni-infected CBA/J mice with moderate splenomegaly syndrome (MSS) or hypersplemomegaly syndrome (HSS). To better understand the development of severe pathology, we compared the two-dimensional differential in-gel electrophoresis (2D-DIGE) proteomic signatures of livers from uninfected mice and mice infected for 6, 8, 12, or 20 weeks and found significant changes in collagen isoforms, interleukin-2 (IL-2), cytokeratin 18, hydroxyproline,S. mansoniphosphoenolpyruvate carboxykinase, major urinary protein isoforms, and peroxiredoxin 6. Cytokeratin 18, hydroxyproline, and connective tissue growth factor (CTGF) were chosen for analysis in mouse and human sera using targeted biochemical assays. Consistent with the liver analysis, cytokeratin 18, CTGF, and hydroxyproline were significantly elevated in sera from mice with HSS compared to those from uninfected mice or mice with MSS. Moreover, cytokeratin 18 and CTGF were found to be markers for subjects with hepatosplenic and intestinal schistosomiasis, respectively, while serum hydroxyproline was a strong indicator of fibrosis for severe HS. These findings indicate that schistosome-associated changes to the liver can be detected in the serum and reveal the potential for cytokeratin 18 to be used as a diagnostic marker for early detection of hepatosplenic schistosomiasis.
Transcriptome Analysis of Avian Pathogenic Escherichia coli O1 in Chicken Serum Reveals Adaptive Responses to Systemic Infection
Authors: Li Ganwu , Tivendale Kelly A. , Liu Peng , Feng Yaping , Wannemuehler Yvonne , Cai Wentong , Mangiamele Paul , Johnson Timothy J. , Constantinidou Chrystala , Penn Charles W. , Nolan Lisa K. 
Published: March 2011

ABSTRACT

Infections of avian pathogenic
Escherichia coli
(APEC) result in annual multimillion-dollar losses to the poultry industry. Despite this, little is known about the mechanisms by which APEC survives and grows in the bloodstream. Thus, the aim of this study was to identify molecular mechanisms enabling APEC to survive and grow in this critical host environment. To do so, we compared the transcriptome of APEC O1 during growth in Luria-Bertani broth and chicken serum. Several categories of genes, predicted to contribute to adaptation and growth in the avian host, were identified. These included several known virulence genes and genes involved in adaptive metabolism, protein transport, biosynthesis pathways, stress resistance, and virulence regulation. Several genes with unknown function, which were localized to pathogenicity islands or APEC O1's large virulence plasmid, pAPEC-O1-ColBM, were also identified, suggesting that they too contribute to survival in serum. The significantly upregulated genes
dnaK
,
dnaJ
,
phoP
, and
ybtA
were subsequently subjected to mutational analysis to confirm their role in conferring a competitive advantage during infection. This genome-wide analysis provides novel insight into processes that are important to the pathogenesis of APEC O1.
Discriminating Lyme Neuroborreliosis from Other Neuroinflammatory Diseases by Levels of CXCL13 in Cerebrospinal Fluid
Authors: van Burgel N. D. , Bakels F. , Kroes A. C. M. , van Dam A. P. 
Published: March 2011

ABSTRACT
CXCL13 in cerebrospinal fluid (CSF) could be an important component for diagnosing Lyme neuroborreliosis (LNB). Levels of intrathecal CXCL13 were determined for 58 LNB patients and 210 controls; sensitivity was 88% and specificity was 89% (cutoff, 250 pg of CXCL13/ml of CSF). Elevated levels of CXCL13 can aid in the diagnosis of LNB, but levels should be interpreted with care.
“Candidatus Neoehrlichia mikurensis” Infection in a Dog from Germany
Authors: Diniz Pedro Paulo V. P. , Schulz Bianka S. , Hartmann Katrin , Breitschwerdt Edward B. 
Published: March 2011

ABSTRACT

“
Candidatus
Neoehrlichia mikurensis” is a new intracellular pathogen associated with human infection and death. “
Candidatus
Neoehrlichia mikurensis” infection in a chronically neutropenic dog from Germany was confirmed by DNA sequencing. The same organism was previously described from ticks and two sick human beings from Germany.
Demonstration of the metaphylactic use of gamithromycin against bacterial pathogens associated with bovine respiratory disease in a multicentre farm trial
Authors: Baggott D. , Casartelli A. , Fraisse F. , Manavella C. , Marteau R. , Rehbein S. , Wiedemann M. , Yoon S. 
Published: March 2011

On five commercial cattle rearing sites across Europe, a total of 802 young cattle at high risk of developing bovine respiratory disease (BRD) associated with the bacterial pathogens Mannheimia haemolytica or Pasteurella multocida and/or Mycoplasma bovis were enrolled into a multicentre, controlled field trial. Half were treated with a single dose of gamithromycin at 6 mg/kg bodyweight by subcutaneous injection and half received an injection of a saline placebo as the control. All animals were observed daily for 14 days for signs of BRD as defined by set criteria. The proportion of metaphylactic preventive treatment successes, defined as animals surviving to day 14 without signs of BRD, in the gamithromycin‐treated group (86 per cent) was significantly (P=0.0012) higher than in the saline‐treated controls (61 per cent). Morbidity among the treated animals was reduced by 64 per cent compared with the controls.
SnowFlock
Authors: Lagar-Cavilla H. Andrés , Whitney Joseph A. , Bryant Roy , Patchin Philip , Brudno Michael , de Lara Eyal , Rumble Stephen M. , Satyanarayanan M. , Scannell Adin 
Published: March 2011

A basic building block of cloud computing is virtualization. Virtual machines (VMs) encapsulate a user’s computing environment and efficiently isolate it from that of other users. VMs, however, are large entities, and no clear APIs exist yet to provide users with programatic, fine-grained control on short time scales.
We present SnowFlock, a paradigm and system for cloud computing that introduces VM cloning as a first-class cloud abstraction. VM cloning exploits the well-understood and effective semantics of UNIX fork. We demonstrate multiple usage models of VM cloning: users can incorporate the primitive in their code, can wrap around existing toolchains via scripting, can encapsulate the API within a parallel programming framework, or can use it to load-balance and self-scale clustered servers.
VM cloning needs to be efficient to be usable. It must efficiently transmit VM state in order to avoid cloud I/O bottlenecks. We demonstrate how the semantics of cloning aid us in realizing its efficiency: state is propagated in parallel to multiple VM clones, and is transmitted during runtime, allowing for optimizations that substantially reduce the I/O load. We show detailed microbenchmark results highlighting the efficiency of our optimizations, and macrobenchmark numbers demonstrating the effectiveness of the different usage models of SnowFlock.
Differentiated storage services
Authors: Mesnier Michael P. , Akers Jason B. 
Published: March 2011

This article presents a Differentiated Storage Services architecture for file and storage systems. By classifying data at the block-level, a filesystem can request that different classes of data (e.g., file, directory, executable, text) be handled with different policies (e.g., low-latency versus highbandwidth), and it is left to the storage system to enforce these policies. Our approach assumes that an I/O classifier can be included in-band with each I/O request (e.g., using a field in the SCSI block command set) and that the policy for each class can be specified out-of-band through the management interface of the storage system.
We describe our prototypes based on Linux Ext3, Windows NTFS, and hybrid storage systems composed of rotating and solid-state disks. With very little modification, filesystems can identify latency sensitive I/O classes (e.g., small files, directories, metadata, and the journal) and request that the storage system provision the solid-state storage for just these classes; and this is simply one of many possibilities. As part of our ongoing work, across a variety of file and storage systems, we are exploring other policies and mechanisms that can be used to improve application performance, reliability, and security.
RFS
Authors: Dong Yuan , Zhu Haiyang , Peng Jinzhan , Wang Fang , Mesnier Michael P. , Wang Dawei , Chan Sun C. 
Published: March 2011

Due to the increasing number of applications (and their data) being placed on mobile devices, access to dependable storage is becoming a key issue in mobile system design -- and cloud storage is becoming an attractive solution. However, this introduces a number of new issues related to unpredictable wireless network connectivity and data privacy over the network.
In this article we present RFS, a wireless-friendly network file system for mobile devices and the cloud. RFS provides deviceaware cache management and client-driven data security and privacy protection. We implement the RFS client in the Linux kernel and the RFS server with Amazon S3 cloud storage, and we employ two new optimizations: server prepush (a server-side data pre-fetching mechanism) and client reintegration (synchronizing a mobile device's cache with the cloud).
The empirical results over wired, WiFi and 3G networks show that RFS achieves good performance compared to Coda and FScache, and it reduces network activity visibly. Further, the privacy overhead is acceptable when RFS is run over wireless networks. We present a case study of booting Android over RFS, thereby demonstrating the ability for RFS to host a full mobile system. Overall, RFS can deliver a good user experience under undependable network conditions, allowing mobile users to seamlessly, and safely, use the cloud for data storage.
Laboring in the Vineyard of Physical Chemistry
Authors: Widom Benjamin 
Published: March 2011

Prologue This is an account mostly of what I have seen and worked on in physical chemistry, from my time in graduate school six decades ago to the present. It is a personal story about kinetics, thermodynamics, and statistical mechanics—in which subjects I continue to be educated, thanks to patient instruction by my students and associates. When I had the invitation from Steve Leone to write this article I said “yes” because (a) “yes” is my default setting; (b) it was a great honor to have been invited to do it; and (c) I was too busy at the time to think about what the consequences of saying “yes” would be. I must now do my best to fulfill my promise.
Physical Activity for Health: What Kind? How Much? How Intense? On Top of What?
Authors: Powell Kenneth E. , Paluch Amanda E. , Blair Steven N. 
Published: March 2011

Physical activity improves health. Different types of activity promote different types of physiologic changes and different health outcomes. A curvilinear reduction in risk occurs for a variety of diseases and conditions across volume of activity, with the steepest gradient at the lowest end of the activity scale. Some activity is better than none, and more is better than some. Even light-intensity activity appears to provide benefit and is preferable to sitting still. When increasing physical activity toward a desired level, small and well-spaced increments will reduce the incidence of adverse events and improve adherence. Prior research on the relationship between activity and health has focused on the value of moderate to vigorous activity on top of an indefinite and shifting baseline. Given emerging evidence that light activities have health benefits and with advances in tools for measuring activities of all intensities, it may be time to shift to zero activity as the conceptual starting point for study.