bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and Safety Study of Posaconazole Intravenous Solution Administered Peripherally to Healthy Subjects
Authors: Kersemaekers Wendy M. , van Iersel Thijs , Nassander Ulla , O'Mara Edward , Waskin Hetty , Caceres Maria , van Iersel Marlou L. P. S. 
Published: December 2014

ABSTRACT

This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (
n
= 45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC
0–∞
]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC
0–∞
was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had ≥1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous posaconazole was otherwise well tolerated. Single doses of i.v. posaconazole were tolerated when given through a peripheral vein over 30 min.
STING Agonists Induce an Innate Antiviral Immune Response against Hepatitis B Virus
Authors: Guo Fang , Han Yanxing , Zhao Xuesen , Wang Jianghua , Liu Fei , Xu Chunxiao , Wei Lai , Jiang Jian-Dong , Block Timothy M. , Guo Ju-Tao , Chang Jinhong 
Published: December 2014

ABSTRACT
Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.
Synergistic Activity of Chloroquine with Fluconazole against Fluconazole-Resistant Isolates of Candida Species
Authors: Li Yali , Wan Zhe , Liu Wei , Li Ruoyu 
Published: December 2014

ABSTRACT

The
in vitro
activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37
Candida
isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant
Candida albicans
isolates, with
Candida krusei
ATCC 6258, and with all 12 fluconazole-resistant
Candida tropicalis
isolates.
Vancomycin-Variable Enterococci Can Give Rise to Constitutive Resistance during Antibiotic Therapy
Authors: Thaker Maulik N. , Kalan Lindsay , Waglechner Nicholas , Eshaghi Alireza , Patel Samir N. , Poutanen Susan , Willey Barbara , Coburn Bryan , McGeer Allison , Low Donald E. , Wright Gerard D. 
Published: December 2014

ABSTRACT
Vancomycin-resistant enterococci (VRE) are notorious clinical pathogens restricting the use of glycopeptide antibiotics in the clinic setting. Routine surveillance to detect VRE isolated from patients relies on PCR bioassays and chromogenic agar-based test methods. In recent years, we and others have reported the emergence of enterococcal strains harboring a “silent” copy of vancomycin resistance genes that confer a vancomycin-susceptible phenotype (vancomycin-susceptible enterococci [VSE]) and thus escape detection using drug sensitivity screening tests. Alarmingly, these strains are able to convert to a resistance phenotype (VSE→VRE) during antibiotic treatment, severely compromising the success of therapy. Such strains have been termed vancomycin-variable enterococci (VVE). We have investigated the molecular mechanisms leading to the restoration of resistance in VVE isolates through the whole-genome sequencing of resistant isolates, measurement of resistance gene expression, and quantification of the accumulation of drug-resistant peptidoglycan precursors. The results demonstrate that VVE strains can revert to a VRE phenotype through the constitutive expression of the vancomycin resistance cassette. This is accomplished through a variety of changes in the DNA region upstream of the resistance genes that includes both a deletion of a likely transcription inhibitory secondary structure and the introduction of a new unregulated promoter. The VSE→VRE transition of VVE can occur in patients during the course of antibiotic therapy, resulting in treatment failure. These VVE strains therefore pose a new challenge to the current regimen of diagnostic tests used for VRE detection in the clinic setting.
The
prrF
-Encoded Small Regulatory RNAs Are Required for Iron Homeostasis and Virulence of Pseudomonas aeruginosa
Authors: Reinhart Alexandria A. , Powell Daniel A. , Nguyen Angela T. , O'Neill Maura , Djapgne Louise , Wilks Angela , Ernst Robert K. , Oglesby-Sherrouse Amanda G. 
Published: December 2014

ABSTRACT

Pseudomonas aeruginosa
is an opportunistic pathogen that requires iron to cause infection, but it also must regulate the uptake of iron to avoid iron toxicity. The iron-responsive PrrF1 and PrrF2 small regulatory RNAs (sRNAs) are part of
P. aeruginosa's
iron regulatory network and affect the expression of at least 50 genes encoding iron-containing proteins. The genes encoding the PrrF1 and PrrF2 sRNAs are encoded in tandem in
P. aeruginosa
, allowing for the expression of a distinct, heme-responsive sRNA named PrrH that appears to regulate genes involved in heme metabolism. Using a combination of growth, mass spectrometry, and gene expression analysis, we showed that the Δ
prrF1
,
2
mutant, which lacks expression of the PrrF and PrrH sRNAs, is defective for both iron and heme homeostasis. We also identified
phuS
, encoding a heme binding protein involved in heme acquisition, and
vreR
, encoding a previously identified regulator of
P. aeruginosa
virulence genes, as novel targets of
prrF
-mediated heme regulation. Finally, we showed that the
prrF
locus encoding the PrrF and PrrH sRNAs is required for
P. aeruginosa
virulence in a murine model of acute lung infection. Moreover, we showed that inoculation with a Δ
prrF1,2
deletion mutant protects against future challenge with wild-type
P. aeruginosa
. Combined, these data demonstrate that the
prrF
-encoded sRNAs are critical regulators of
P. aeruginosa
virulence.
The Identification and Functional Characterization of WxL Proteins from Enterococcus faecium Reveal Surface Proteins Involved in Extracellular Matrix Interactions
Authors: Galloway-Peña Jessica R. , Liang Xiaowen , Singh Kavindra V. , Yadav Puja , Chang Chungyu , La Rosa Sabina Leanti , Shelburne Samuel , Ton-That Hung , Höök Magnus , Murray Barbara E. 
Published: December 2014

ABSTRACT

The WxL domain recently has been identified as a novel cell wall binding domain found in numerous predicted proteins within multiple Gram-positive bacterial species. However, little is known about the function of proteins containing this novel domain. Here, we identify and characterize 6
Enterococcus faecium
proteins containing the WxL domain which, by reverse transcription-PCR (RT-PCR) and genomic analyses, are located in three similarly organized operons, deemed WxL loci A, B, and C. Western blotting, electron microscopy, and enzyme-linked immunosorbent assays (ELISAs) determined that genes of WxL loci A and C encode antigenic, cell surface proteins exposed at higher levels in clinical isolates than in commensal isolates. Secondary structural analyses of locus A recombinant WxL domain-containing proteins found they are rich in β-sheet structure and disordered segments. Using Biacore analyses, we discovered that recombinant WxL proteins from locus A bind human extracellular matrix proteins, specifically type I collagen and fibronectin. Proteins encoded by locus A also were found to bind to each other, suggesting a novel cell surface complex. Furthermore, bile salt survival assays and animal models using a mutant from which all three WxL loci were deleted revealed the involvement of WxL operons in bile salt stress and endocarditis pathogenesis. In summary, these studies extend our understanding of proteins containing the WxL domain and their potential impact on colonization and virulence in
E. faecium
and possibly other Gram-positive bacterial species.
Variations in O-Antigen Biosynthesis and O-Acetylation Associated with Altered Phage Sensitivity in Escherichia coli 4s
Authors: Knirel Yuriy A. , Prokhorov Nikolai S. , Shashkov Alexander S. , Ovchinnikova Olga G. , Zdorovenko Evelina L. , Liu Bin , Kostryukova Elena S. , Larin Andrey K. , Golomidova Alla K. , Letarov Andrey V. 
Published: December 2014

ABSTRACT

The O polysaccharide of the lipopolysaccharide (O antigen) of Gram-negative bacteria often serves as a receptor for bacteriophages that can make the phage dependent on a given O-antigen type, thus supporting the concept of the adaptive significance of the O-antigen variability in bacteria. The O-antigen layer also modulates interactions of many bacteriophages with their hosts, limiting the access of the viruses to other cell surface receptors. Here we report variations of O-antigen synthesis and structure in an environmental
Escherichia coli
isolate, 4s, obtained from horse feces, and its mutants selected for resistance to bacteriophage G7C, isolated from the same fecal sample. The 4s O antigen was found to be serologically, structurally, and genetically related to the O antigen of
E. coli
O22, differing only in side-chain α-
d
-glucosylation in the former, mediated by a
gtr
locus on the chromosome. Spontaneous mutations of
E. coli
4s occurring with an unusually high frequency affected either O-antigen synthesis or O-acetylation due to the inactivation of the gene encoding the putative glycosyltransferase WclH or the putative acetyltransferase WclK, respectively, by the insertion of IS
1
-like elements. These mutations induced resistance to bacteriophage G7C and also modified interactions of
E. coli
4s with several other bacteriophages conferring either resistance or sensitivity to the host. These findings suggest that O-antigen synthesis and O-acetylation can both ensure the specific recognition of the O-antigen receptor following infection by some phages and provide protection of the host cells against attack by other phages.
Resuscitation-Promoting Factors Are Cell Wall-Lytic Enzymes with Important Roles in the Germination and Growth of Streptomyces coelicolor
Authors: Sexton Danielle L. , St-Onge Renée J. , Haiser Henry J. , Yousef Mary R. , Brady Lauren , Gao Chan , Leonard Jacqueline , Elliot Marie A. 
Published: December 2014

ABSTRACTDormancy is a common strategy adopted by bacterial cells as a means of surviving adverse environmental conditions. ForStreptomycesbacteria, this involves developing chains of dormant exospores that extend away from the colony surface. Both spore formation and subsequent spore germination are tightly controlled processes, and while significant progress has been made in understanding the underlying regulatory and enzymatic bases for these, there are still significant gaps in our understanding. One class of proteins with a potential role in spore-associated processes are the so-called resuscitation-promoting factors, or Rpfs, which in other actinobacteria are needed to restore active growth to dormant cell populations. The model speciesStreptomyces coelicolorencodes five Rpf proteins (RpfA to RfpE), and here we show that these proteins have overlapping functions during growth. Collectively, theS. coelicolorRpfs promote spore germination and are critical for growth under nutrient-limiting conditions. Previous studies have revealed structural similarities between the Rpf domain and lysozyme, and ourin vitrobiochemical assays revealed various levels of peptidoglycan cleavage capabilities for each of these fiveStreptomycesenzymes. Peptidoglycan remodeling by enzymes such as these must be stringently governed so as to retain the structural integrity of the cell wall. Our results suggest that one of the Rpfs, RpfB, is subject to a unique mode of enzymatic autoregulation, mediated by a domain of previously unknown function (DUF348) located within the N terminus of the protein; removal of this domain led to significantly enhanced peptidoglycan cleavage.
Milk intake, height and body mass index in preschool children
Authors: DeBoer Mark D , Agard Hannah E , Scharf Rebecca J 
Published: December 2014

ObjectivesTo evaluate links between the volume of milk consumed and weight and height status in children aged 4 and 5 years.DesignWe analysed data from 8950 children followed up as part of the Early Childhood Longitudinal Survey, Birth cohort, a nationally representative cohort of children. We used linear and logistic regression to assess associations of daily servings of milk intake at age 4 years with z-scores of body mass index (BMI), height and weight-for-height at 4 and 5 years, adjusted for sex, race/ethnicity, socioeconomic status and type of milk consumed.ResultsAmong children who drank milk at age 4 years, higher milk consumption was associated with higher z-scores of BMI, height and weight-for-height at 4 years (all p<0.05). This corresponded to differences between children drinking <1 and ≥4 milk servings daily of approximately 1 cm in height and 0.15 kg in weight. By age 5 years, only the association with height remained significant (p<0.001). At 4 years, children drinking ≥3 servings of milk daily were more likely to be overweight/obese (BMI≥85th percentile) than those drinking 0.5–2 servings of milk daily (adjusted OR 1.16 (95% CI 1.02 to 1.32) p=0.02).ConclusionsIn a cohort of children at age 4 years, the volume of milk consumed was associated with higher weight status and taller stature, while at 5 years, higher milk consumption continued to be associated with taller stature. Given higher odds of overweight/obesity with milk consumption ≥3 servings daily, this study supports current American Academy of Pediatrics recommendations that pre-school children consume two milk servings daily.
Advertisements of follow-on formula and their perception by pregnant women and mothers in Italy
Authors: Cattaneo Adriano , Pani Paola , Carletti Claudia , Guidetti Margherita , Mutti Valentina , Guidetti Cecilia , Knowles Alessandra 
Published: December 2014

ObjectiveTo assess how follow-on formula milks for infants aged 6–12 months are presented to and understood by mothers.DesignA quantitative and qualitative cross-sectional study including (1) an analysis of advertisements in three magazines for parents; (2) in-depth semistructured qualitative interviews to pregnant women on their perception of two advertisements for follow-on formula and (3) self-administered questionnaires for mothers to explore their exposure to and perception of formula advertisements.ParticipantsEighty pregnant women 32–36 weeks of gestation with no previous children and 562 mothers of children <3 years old.SettingMaternal and child health centres in eight cities of Italy.ResultsAdvertisements of formula (n=89) represented about 7% of all advertisements in the three magazines, the majority (58%) being for follow-on formula. Advertisements were parent-oriented, aimed at helping parents solve health problems of their babies or at eliciting good feelings, or both. The qualitative interviews to pregnant women showed inability to define the advertised products at first glance due to the ambiguity of the numeral 2 and the presumed age of the portrayed baby; this inability did not disappear after carefully viewing the advertisements and reading the text. When asked in the self-administered questionnaires whether they had ever come across advertisements of infant formula, 81% of mothers reported that they had, despite the legal inexistence of such advertisements, and 65% thought that it was for a product to be used from birth.ConclusionsAdvertisements of follow-on formula are perceived by pregnant women and mothers as promoting infant formula.
Attitudes, access and anguish: a qualitative interview study of staff and patients’ experiences of diabetic retinopathy screening
Authors: Hipwell A E , Sturt J , Lindenmeyer A , Stratton I , Gadsby R , O'Hare P , Scanlon P H 
Published: December 2014

ObjectiveTo examine the experiences of patients, health professionals and screeners; their interactions with and understandings of diabetic retinopathy screening (DRS); and how these influence uptake.DesignPurposive, qualitative design using multiperspectival, semistructured interviews and thematic analysis.SettingThree UK Screening Programme regions with different service-delivery modes, minority ethnic and deprivation levels across rural, urban and inner-city areas, in general practitioner practices and patients’ homes.Participants62 including 38 patients (22 regular-screening attenders, 16 non-regular attenders) and 24 professionals (15 primary care professionals and 9 screeners).ResultsAntecedents to attendance included knowledge about diabetic retinopathy and screening; antecedents to non-attendance included psychological, pragmatic and social factors. Confusion between photographs taken at routine eye tests and DRS photographs was identified. The differing regional invitation methods and screening locations were discussed, with convenience and transport safety being over-riding considerations for patients. Some patients mentioned significant pain and visual disturbance from mydriasis drops as a deterrent to attendance.ConclusionsIn this, the first study to consider multiperspectival experiential accounts, we identified that proactive coordination of care involving patients, primary care and screening programmes, prior to, during and after screening is required. Multiple factors, prior to, during and after screening, are involved in the attendance and non-attendance for DRS. Further research is needed to establish whether patient self-management educational interventions and the pharmacological reformulation of shorter acting mydriasis drops, may improve uptake of DRS. This might, in turn, reduce preventable vision loss and its associated costs to individuals and their families, and to health and social care providers, reducing current inequalities.
Geodynamic processes in the Andes of Central Chile and Argentina: an introduction
Authors: Sepúlveda Sergio A. , Giambiagi Laura B. , Moreiras Stella M. , Pinto Luisa , Tunik Maisa , Hoke Gregory D. , Farías Marcelo 
Published: December 2014

Abstract

The Andes, the world's largest non-collisional orogen, is considered the paradigm for geodynamic processes associated with the subduction of an oceanic plate below a continental plate margin. In the framework of UNESCO-sponsored IGCP 586-Y project, this Special Publication includes state-of-the-art reviews and original articles from a range of Earth Science disciplines that investigate the complex interactions of tectonics and surface processes in the subduction-related orogen of the Andes of central Chile and Argentina (
c.
27–39°S). This introduction provides the geological context of the transition from flat slab to normal subduction angles, where this volume is focused, along with a brief description of the individual contributions ranging from internal geodynamics and tectonics, Quaternary tectonics and related geohazards, to landscape evolution of this particular segment of the Andes.
The artist as geotourist: Eugene von Guérard and the seminal sites of early volcanic research in Europe and Australia
Authors: Pullin Ruth 
Published: December 2014

Abstract
The career of the Austrian-born landscape painter Eugene von Guérard (1811–1901) was defined by his travels, which took him to Italy and Germany in the 1830s and 1840s and to Australia and New Zealand between 1852 and 1882. Today he is recognized as one of Australia's greatest nineteenth-century landscape painters. His formative years coincided with the emergence of geology as an independent scientific discipline and a growing awareness in the wider community of the role played by volcanic activity and other geological processes in the formation of the Earth's geomorphology. This new understanding was particularly pertinent to landscape painters, whose very subject was the form of the land; in Germany, where von Guérard trained and worked between 1838 and 1852, its relevance for landscape painters was emphasized by the influential natural scientist Alexander von Humboldt and the scientist, landscape painter and art theorist Carl Gustav Carus. They argued that the artist should paint from a geologically informed perspective. Von Guérard's interest in volcanic geology was sparked by his experiences in southern Italy, consolidated in Germany on expeditions through the Harz and Eifel regions and then fully realized in response to the landscapes of southeastern Australia. Through his informed portrayal of sites of geological significance in each hemisphere and through the cultural value invested in them as a consequence of his depiction of them, von Guérard epitomized that recently conceived construct: the geotourist.