bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of the HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068, against CD4-Independent Viruses and HIV-1 Envelopes Resistant to Other Entry Inhibitors
Authors: Li Zhufang , Zhou Nannan , Sun Yongnian , Ray Neelanjana , Lataillade Max , Hanna George J. , Krystal Mark 
Published: June 2013

ABSTRACT

BMS-626529 is a novel small-molecule HIV-1 attachment inhibitor active against both CCR5- and CXCR4-tropic viruses. BMS-626529 functions by preventing gp120 from binding to CD4. A prodrug of this compound, BMS-663068, is currently in clinical development. As a theoretical resistance pathway to BMS-663068 could be the development of a CD4-independent phenotype, we examined the activity of BMS-626529 against CD4-independent viruses and investigated whether resistance to BMS-626529 could be associated with a CD4-independent phenotype. Finally, we evaluated whether cross-resistance exists between BMS-626529 and other HIV-1 entry inhibitors. Two laboratory-derived envelopes with a CD4-independent phenotype (one CXCR4 tropic and one CCR5 tropic), five envelopes from clinical isolates with preexisting BMS-626529 resistance, and several site-specific mutant BMS-626529-resistant envelopes were examined for their dependence on CD4 for infectivity or susceptibility to BMS-626529. Viruses resistant to other entry inhibitors (enfuvirtide, maraviroc, and ibalizumab) were also examined for susceptibility to BMS-626529. Both CD4-independent laboratory isolates retained sensitivity to BMS-626529 in CD4
−
cells, while HIV-1 envelopes from viruses resistant to BMS-626529 exhibited no evidence of a CD4-independent phenotype. BMS-626529 also exhibited inhibitory activity against ibalizumab- and enfuvirtide-resistant envelopes. While there appeared to be some association between maraviroc resistance and reduced susceptibility to BMS-626529, an absolute correlation cannot be presumed, since some CCR5-tropic maraviroc-resistant envelopes remained sensitive to BMS-626529. Clinical use of the prodrug BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus. No cross-resistance between BMS-626529 and other HIV entry inhibitors was observed, which could allow for sequential or concurrent use with different classes of entry inhibitors.
Multicenter Study of High-Dose Daptomycin for Treatment of Enterococcal Infections
Authors: Casapao Anthony M. , Kullar Ravina , Davis Susan L. , Levine Donald P. , Zhao Jing J. , Potoski Brian A. , Goff Debra A. , Crank Christopher W. , Segreti John , Sakoulas George , Cosgrove Sara E. , Rybak Michael J. 
Published: June 2013

ABSTRACT

Enterococci are among the leading pathogens isolated in hospital-acquired infections. Current antimicrobial options for vancomycin-resistant enterococci (VRE) are limited. Prior data suggest that daptomycin at >6 mg/kg of body weight/day may be used to treat enterococcal infections. We retrospectively evaluated the effectiveness and safety of high-dose daptomycin (HD-daptomycin) therapy (>6 mg/kg) in a multicenter cohort of adult patients with enterococcal infections to describe the characteristics and outcomes. Two hundred forty-five patients were evaluated.
Enterococcus faecium
was identified in 175 (71%), followed by
Enterococcus faecalis
in 49 (20%) and
Enterococcus
spp. in 21 (9%); overall, 204 (83%) isolates were VRE. Enterococcal infections included bacteremia (173, 71%) and intra-abdominal (35, 14%) and bone and joint (25, 10%) infections. The median dosage and duration of HD-daptomycin were 8.2 mg/kg/day (interquartile range [IQR], 7.7 to 9.7) and 10 days (IQR, 6 to 15), respectively. The overall clinical success rate was 89% (193/218), and microbiological eradication was observed in 93% (177/191) of patients. The median time to clearance of blood cultures on HD-daptomycin was 3 days (IQR, 2 to 5). The 30-day all-cause mortality rate was 27%, and 5 (2%) patients developed daptomycin-nonsusceptible enterococcal strains while on HD-daptomycin. Seven patients (3%) had creatine phosphokinase (CPK) elevation, yet no HD-daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic. Overall, there was a high frequency of clinical success and microbiological eradication in patients treated with HD-daptomycin for enterococcal infections, even in patients with complicated and difficult-to-treat infections. No adverse event-related discontinuation of HD-daptomycin was noted. HD-daptomycin may be an option for the treatment of enterococcal infections.
Myxomavirus-Derived Serpin Prolongs Survival and Reduces Inflammation and Hemorrhage in an Unrelated Lethal Mouse Viral Infection
Authors: Chen Hao , Zheng Donghang , Abbott Jeff , Liu Liying , Bartee Mee Y. , Long Maureen , Davids Jennifer , Williams Jennifer , Feldmann Heinz , Strong James , Grau Katrina R. , Tibbetts Scott , Macaulay Colin , McFadden Grant , Thoburn Robert , Lomas David A. , Spinale Francis G. , Virgin Herbert W. , Lucas Alexandra 
Published: June 2013

ABSTRACT

Lethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [DIC]), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normal
ser
ine
p
rotease
in
hibitor (serpin) regulation. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits clotting factor X (fX) and thrombolytic tissue- and urokinase-type plasminogen activators (tPA and uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine gammaherpesvirus 68 (MHV68) infection in gamma interferon receptor (IFN-γR) knockout mice, a model for lethal inflammatory vasculitis. Treatment of MHV68-infected mice with neuroserpin, a mammalian serpin that inhibits only tPA and uPA, was ineffective. Serp-1 reduced virus load, lung hemorrhage, and aortic, lung, and colon inflammation in MHV68-infected mice and also reduced virus load. Neuroserpin suppressed a wide range of immune spleen cell responses after MHV68 infection, while Serp-1 selectively increased CD11c
+
splenocytes (macrophage and dendritic cells) and reduced CD11b
+
tissue macrophages. Serp-1 altered gene expression for coagulation and inflammatory responses, whereas neuroserpin did not. Serp-1 treatment was assessed in a second viral infection, mouse-adapted Zaire ebolavirus in wild-type BALB/c mice, with improved survival and reduced tissue necrosis. In summary, treatment with this unique myxomavirus-derived serpin suppresses systemic serine protease and innate immune responses caused by unrelated lethal viral infections (both RNA and DNA viruses), providing a potential new therapeutic approach for treatment of lethal viral sepsis.
Na
+
/H
+
Antiport Is Essential for Yersinia pestis Virulence
Authors: Minato Yusuke , Ghosh Amit , Faulkner Wyatt J. , Lind Erin J. , Schesser Bartra Sara , Plano Gregory V. , Jarrett Clayton O. , Hinnebusch B. Joseph , Winogrodzki Judith , Dibrov Pavel , Häse Claudia C. 
Published: June 2013

ABSTRACT

Na
+
/H
+
antiporters are ubiquitous membrane proteins that play a central role in the ion homeostasis of cells. In this study, we examined the possible role of Na
+
/H
+
antiport in
Yersinia pestis
virulence and found that
Y. pestis
strains lacking the major Na
+
/H
+
antiporters, NhaA and NhaB, are completely attenuated in an
in vivo
model of plague. The
Y. pestis
derivative strain lacking the
nhaA
and
nhaB
genes showed markedly decreased survival in blood and blood serum
ex vivo
. Complementation of either
nhaA
or
nhaB
in
trans
restored the survival of the
Y. pestis nhaA nhaB
double deletion mutant in blood. The
nhaA nhaB
double deletion mutant also showed inhibited growth in an artificial serum medium, Opti-MEM, and a rich LB-based medium with Na
+
levels and pH values similar to those for blood. Taken together, these data strongly suggest that intact Na
+
/H
+
antiport is indispensable for the survival of
Y. pestis
in the bloodstreams of infected animals and thus might be regarded as a promising noncanonical drug target for infections caused by
Y. pestis
and possibly for those caused by other blood-borne bacterial pathogens.
Identification of Salmonella enterica Serovar Pullorum Antigenic Determinants Expressed
In Vivo
Authors: Li Qiuchun , Hu Yachen , Chen Jing , Liu Zhicheng , Han Jun , Sun Lin , Jiao Xinan 
Published: June 2013

ABSTRACT

Salmonella enterica
serovar Pullorum affecting poultry causes pullorum disease and results in severe economic loss in the poultry industry. Currently, it remains a major threat in countries with poor poultry surveillance and no efficient control measures. As
S
. Pullorum could induce strong humoral immune responses, we applied an immunoscreening technique, the
in vivo
-induced antigen technology (IVIAT), to identify immunogenic bacterial proteins expressed or upregulated during
S
. Pullorum infection. Convalescent-phase sera from chickens infected with
S
. Pullorum were pooled, adsorbed against antigens expressed
in vitro
, and used to screen an
S
. Pullorum genomic expression library. Forty-five proteins were screened out, and their functions were implicated in molecular biosynthesis and degradation, transport, metabolism, regulation, cell wall synthesis and antibiotic resistance, environmental adaptation, or putative functions. In addition, 11 of these 45 genes were assessed for their differential expression by quantitative real-time reverse transcription-PCR (RT-PCR), revealing that 9 of 11 genes were upregulated to different degrees under
in vivo
conditions, especially the regulator of virulence determinants,
phoQ
. Then, four
in vivo
-induced proteins (ShdA, PhoQ, Cse3, and PbpC) were tested for their immunoreactivity in 28 clinical serum samples from chickens infected with
S
. Pullorum. The rate of detection of antibodies against ShdA reached 82% and was the highest among these proteins. ShdA is a host colonization factor known to be upregulated
in vivo
and related to the persistence of
S
. Typhimurium in the intestine. Furthermore, these antigens identified by IVIAT warrant further evaluation for their contributions to pathogenesis, and more potential roles, such as diagnostic, therapeutic, and preventive uses, need to be developed in future studies.
Genetic Analysis of the Role of
yfiR
in the Ability of Escherichia coli CFT073 To Control Cellular Cyclic Dimeric GMP Levels and To Persist in the Urinary Tract
Authors: Raterman Erica L. , Shapiro Daniel D. , Stevens Daniel J. , Schwartz Kevin J. , Welch Rodney A. 
Published: June 2013

ABSTRACT

During urinary tract infections (UTIs), uropathogenic
Escherichia coli
must maintain a delicate balance between sessility and motility to achieve successful infection of both the bladder and kidneys. Previous studies showed that cyclic dimeric GMP (c-di-GMP) levels aid in the control of the transition between motile and nonmotile states in
E. coli
. The
yfiRNB
locus in
E. coli
CFT073 contains genes for YfiN, a diguanylate cyclase, and its activity regulators, YfiR and YfiB. Deletion of
yfiR
yielded a mutant that was attenuated in both the bladder and the kidneys when tested in competition with the wild-type strain in the murine model of UTI. A double
yfiRN
mutant was not attenuated in the mouse model, suggesting that unregulated YfiN activity and likely increased cytoplasmic c-di-GMP levels cause a survival defect. Curli fimbriae and cellulose production were increased in the
yfiR
mutant. Expression of
yhjH
, a gene encoding a proven phosphodiesterase, in CFT073 Δ
yfiR
suppressed the overproduction of curli fimbriae and cellulose and further verified that deletion of
yfiR
results in c-di-GMP accumulation. Additional deletion of
csgD
and
bcsA
, genes necessary for curli fimbriae and cellulose production, respectively, returned colonization levels of the
yfiR
deletion mutant to wild-type levels. Peroxide sensitivity assays and iron acquisition assays displayed no significant differences between the
yfiR
mutant and the wild-type strain. These results indicate that dysregulation of c-di-GMP production results in pleiotropic effects that disable
E. coli
in the urinary tract and implicate the c-di-GMP regulatory system as an important factor in the persistence of uropathogenic
E. coli in vivo
.
Republished: Building a culture of safety through team training and engagement
Authors: Thomas Lily , Galla Catherine 
Published: June 2013

Abstract
Medical errors continue to occur despite multiple strategies devised for their prevention. Although many safety initiatives lead to improvement, they are often short lived and unsustainable. Our goal was to build a culture of patient safety within a structure that optimised teamwork and ongoing engagement of the healthcare team. Teamwork impacts the effectiveness of care, patient safety and clinical outcomes, and team training has been identified as a strategy for enhancing teamwork, reducing medical errors and building a culture of safety in healthcare. Therefore, we implemented Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), an evidence-based framework which was used for team training to create transformational and/or incremental changes; facilitating transformation of organisational culture, or solving specific problems. To date, TeamSTEPPS (TS) has been implemented in 14 hospitals, two Long Term Care Facilities, and outpatient areas across the North Shore LIJ Health System. 32 150 members of the healthcare team have been trained. TeamSTEPPS was piloted at a community hospital within the framework of the health system's organisational care delivery model, the Collaborative Care Model to facilitate sustainment. AHRQ's Hospital Survey on Patient Safety Culture, (HSOPSC), was administered before and after implementation of TeamSTEPPS, comparing the perception of patient safety by the heathcare team. Pilot hospital results of HSOPSC show significant improvement from 2007 (pre-TeamSTEPPS) to 2010. System-wide results of HSOPSC show similar trends to those seen in the pilot hospital. Valuable lessons for organisational success from the pilot hospital enabled rapid spread of TeamSTEPPS across the rest of the health system.
Republished: Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime
Authors: Forsberg Lars Anders , Absher Devin , Dumanski Jan Piotr 
Published: June 2013

Abstract
The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease—the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders.
RADIATION STUDIES FOR THE Mu2e EXPERIMENT: A REVIEW
Authors: PRONSKIKH V. S. 
Published: June 2013

The Mu2e experiment being designed at Fermilab will be searching for a rare event — conversion of muon into electron in the field of a nucleus without emission of neutrinos — observation of which would provide unambiguous evidence for physics beyond the Standard Model, making use of an 8 GeV 8 kW proton beam. As an experiment to be performed at the Intensity Frontier, taking advantage of high-intensity proton beams, the Mu2e experimental setup will be residing in a harsh radiation environment created by secondary particle fluxes. Radiation quantities in different parts of the Mu2e apparatus, such as neutron flux, peak power density, displacements per atom (DPA), absorbed dose, dynamic heat load simulated using the MARS15 code are reviewed in this work. Radiation levels and requirements for Heat and Radiation Shield (HRS), Transport Solenoid (TS), residual dose and decay heat from the Mu2e target, beam dump design, rates in Cosmic Ray Veto (CRV) counters as well as stopping target monitor (STM) are considered. Airflow, surface and ground water activation are estimated. Recent developments in the MARS15 DPA model applied in this work are described, their consequences are discussed.
First-Order Logic on Higher-Order Nested Pushdown Trees
Authors: Kartzow Alexander 
Published: June 2013

We introduce a new hierarchy of
higher-order nested pushdown trees
generalising Alur et al.’s concept of nested pushdown trees. Nested pushdown trees are useful representations of control flows in the verification of programs with recursive calls of first-order functions. Higher-order nested pushdown trees are expansions of unfoldings of graphs generated by higher-order pushdown systems. Moreover, the class of nested pushdown trees of level
n
is uniformly first-order interpretable in the class of collapsible pushdown graphs of level
n
+ 1. The relationship between the class of higher-order pushdown graphs and the class of collapsible higher-order pushdown graphs is not very well understood. We hope that the further study of the nested pushdown tree hierarchy leads to a better understanding of these two hierarchies. In this article, we are concerned with the first-order model checking problem on higher-order nested pushdown trees. We show that the first-order model checking on the first two levels of this hierarchy is decidable. Moreover, we obtain an alternating 2-EXPTIME algorithm for the class of nested pushdown trees of level 1. The proof technique involves a pseudo-local analysis of strategies in the Ehrenfeucht-Fraïssé games on two identical copies of a nested pushdown tree. Ordinary locality arguments in the spirit of Gaifman’s lemma do not apply here because nested pushdown trees tend to have small diameters. We introduce the notion of relevant ancestors which provide a sufficient description of the
FO
k
-type of each element in a higher-order nested pushdown tree. The local analysis of these ancestors allows us to prove the existence of restricted winning strategies in the Ehrenfeucht-Fraïssé game. These strategies are then used to create a first-order model checking algorithm.
Contribution of Flow Cytometry to Acute Leukemia Classification in Tunisia
Authors: Feki S. , El Omri H. , Laatiri M. A. , Ennabli S. , Boukef K. , Jenhani F. 
Published: June 2013

The precision of immunological characterization of leukemias was improved by a certain number of technical innovations, particularly hybridoma production and standardization, resulting in monoclonal antibodies and definition of recognised cellular antigens (designated by CD: Cluster of Differentiation).The aim of this work was to determine the immunophenotyping profile of patients with leukemia, by means of a flow cytometric method: 66 blood samples coming from leukemic persons in the Sahel region were studied by flow cytometry, using about thirty monoclonal antibodies all marked with a fluorochrome, in one or two colour systems to assess their distribution according to type (lymphoid B or T / myeloid) and age, and to search for possible co‐expressions of markers of different lineages.The marked preponderance of childhood B‐ALL in our series is, at least partly, attributable to the age distribution of the Tunisian population. In agreement with studies from other countries, the majority of AML cases occurred among adults. A high proportion of AML cases in our series co‐expressed markers of other lineages. Overall, accurate classification of acute leukemias was possible from a simple peripheral blood sample in 62 of 66 cases (93.9%).
C282Y and H63D Mutation Frequencies in a Population from Central Spain
Authors: Alvarez S. , Mesa M. S. , Bandrés F. , Arroyo E. 
Published: June 2013

Objectives: To determine the frequency of hereditary hemochromatosis gene mutations, C282Y and H63D, from 125 autochthonous blood donors originating from a Central region of Spain, to provide epidemiological data about HFE gene in the Iberian Peninsula.Methods: DNA extracted from blood samples was analyzed by PCR‐RFLP. Restriction enzimes were Snab I and Bcl I for C282Y and H63D, respectively. Results were visualized with Ethidium Bromide staining after gel electrophoresis.Results and discussion: C282Y frequency was 0.02 and that of H63D was 0.16. Result for C282Y mutation falls within the range of variation of the Mediterranean populations. H63D frequency agrees with those reported for other European populations. In both cases frequencies obtained are the lowest of compared Spanish data.Conclusions: This study is useful to compare expected versus presented C282Y and H63D frequencies in Spanish populations and to contribute to the knowledge of Spanish variability, rarely analyzed until now for HFE gene mutations.
Extracellular RNA Liberates Tumor Necrosis Factor-α to Promote Tumor Cell Trafficking and Progression
Authors: Fischer Silvia , Gesierich Sabine , Griemert Barbara , Schänzer Anne , Acker Till , Augustin Hellmut G. , Olsson Anna-Karin , Preissner Klaus T. 
Published: June 2013

Abstract
Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-α from macrophages in a manner requiring activation of the TNF-α–converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-α release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-κB pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-α release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. Cancer Res; 73(16); 5080–9. ©2013 AACR.