bluuebunny/crossref_metadata_2025_split huggingface dataset:
Limitations of Murine Models for Assessment of Antibody-Mediated Therapies or Vaccine Candidates against Staphylococcus epidermidis Bloodstream Infection
Authors: Cole Leah E. , Zhang Jinrong , Kesselly Augustus , Anosova Natalie G. , Lam Hubert , Kleanthous Harry , Yethon Jeremy A. 
Published: February 2016

ABSTRACT

Staphylococcus epidermidis
is normally a commensal colonizer of human skin and mucus membranes, but, due to its ability to form biofilms on indwelling medical devices, it has emerged as a leading cause of nosocomial infections. Bacteremia or bloodstream infection is a frequent and costly complication resulting from biofilm fouling of medical devices. Our goal was to develop a murine model of
S. epidermidis
infection to identify potential vaccine targets for the prevention of
S. epidermidis
bacteremia. However, assessing the contribution of adaptive immunity to protection against
S. epidermidis
challenge was complicated by a highly efficacious innate immune response in mice. Naive mice rapidly cleared
S. epidermidis
infections from blood and solid organs, even when the animals were immunocompromised. Cyclophosphamide-mediated leukopenia reduced the size of the bacterial challenge dose required to cause lethality but did not impair clearance after a nonlethal challenge. Nonspecific innate immune stimulation, such as treatment with a Toll-like receptor 4 (TLR4) agonist, enhanced bacterial clearance. TLR2 signaling was confirmed to accelerate the clearance of
S. epidermidis
bacteremia, but TLR2
−/−
mice could still resolve a bloodstream infection. Furthermore, TLR2 signaling played no role in the clearance of bacteria from the spleen. In conclusion, these data suggest that
S. epidermidis
bloodstream infection is cleared in a highly efficient manner that is mediated by both TLR2-dependent and -independent innate immune mechanisms. The inability to establish a persistent infection in mice, even in immunocompromised animals, rendered these murine models unsuitable for meaningful assessment of antibody-mediated therapies or vaccine candidates.
Mice with Genetic Deletion of Group VIA Phospholipase A
2
β Exhibit Impaired Macrophage Function and Increased Parasite Load in Trypanosoma cruzi-Induced Myocarditis
Authors: Sharma Janhavi , Blase Jennifer R. , Hoft Daniel F. , Marentette John O. , Turk John , McHowat Jane 
Published: February 2016

ABSTRACT

Trypanosoma cruzi
infection, which is the etiological agent of Chagas disease, is associated with intense inflammation during the acute and chronic phases. The pathological progression of Chagas disease is influenced by the infiltration and transmigration of inflammatory cells across the endothelium to infected tissues, which are carefully regulated processes involving several molecular mediators, including adhesion molecules and platelet-activating factor (PAF). We have shown that PAF production is dependent upon calcium-independent group VIA phospholipase A
2
β (iPLA
2
β) following infection of human coronary artery endothelial cells (HCAECs) with
T. cruzi
, suggesting that the absence of iPLA
2
β may decrease the recruitment of inflammatory cells to the heart to manage parasite accumulation. Cardiac endothelial cells isolated from iPLA
2
β-knockout (iPLA
2
β-KO) mice infected with
T. cruzi
demonstrated decreased PAF production compared to that by cells isolated from wild-type (WT) mice but demonstrated increases in adhesion molecule expression similar to those seen in WT mice. Myocardial inflammation in iPLA
2
β-KO mice infected with
T. cruzi
was similar in severity to that in WT mice, but the iPLA
2
β-KO mouse myocardium contained more parasite pseudocysts. Upon activation, macrophages from iPLA
2
β-KO mice produced significantly less nitric oxide (NO) and caused less
T. cruzi
inhibition than macrophages from wild-type mice. Thus, the absence of iPLA
2
β activity does not influence myocardial inflammation, but iPLA
2
β is essential for
T. cruzi
clearance.
Molecular Characterization of the Vacuolating Autotransporter Toxin in Uropathogenic Escherichia coli
Authors: Nichols Katie B. , Totsika Makrina , Moriel Danilo G. , Lo Alvin W. , Yang Ji , Wurpel Daniël J. , Rossiter Amanda E. , Strugnell Richard A. , Henderson Ian R. , Ulett Glen C. , Beatson Scott A. , Schembri Mark A. 
Published: February 2016

ABSTRACT

The vacuolating autotransporter toxin (Vat) contributes to uropathogenic
Escherichia coli
(UPEC) fitness during systemic infection. Here, we characterized Vat and investigated its regulation in UPEC. We assessed the prevalence of
vat
in a collection of 45 UPEC urosepsis strains and showed that it was present in 31 (68%) of the isolates. The isolates containing the
vat
gene corresponded to three major
E. coli
sequence types (ST12, ST73, and ST95), and these strains secreted the Vat protein. Further analysis of the
vat
genomic locus identified a conserved gene located directly downstream of
vat
that encodes a putative MarR-like transcriptional regulator; we termed this gene
vatX
. The
vat-vatX
genes were present in the UPEC reference strain CFT073, and reverse transcriptase PCR (RT-PCR) revealed that the two genes are cotranscribed. Overexpression of
vatX
in CFT073 led to a 3-fold increase in
vat
gene transcription. The
vat
promoter region contained three putative nucleation sites for the global transcriptional regulator histone-like nucleoid structuring protein (H-NS); thus, the
hns
gene was mutated in CFT073 (to generate CFT073
hns
). Western blot analysis using a Vat-specific antibody revealed a significant increase in Vat expression in CFT073
hns
compared to that in wild-type CFT073. Direct H-NS binding to the
vat
promoter region was demonstrated using purified H-NS in combination with electrophoresis mobility shift assays. Finally, Vat-specific antibodies were detected in plasma samples from urosepsis patients infected by
vat
-containing UPEC strains, demonstrating that Vat is expressed during infection. Overall, this study has demonstrated that Vat is a highly prevalent and tightly regulated immunogenic serine protease autotransporter protein of
Enterobacteriaceae
(SPATE) secreted by UPEC during infection.

IMPORTANCE
Uropathogenic
Escherichia coli
(UPEC) is the major cause of hospital- and community-acquired urinary tract infections. The vacuolating autotransporter toxin (Vat) is a cytotoxin known to contribute to UPEC fitness during murine sepsis infection. In this study, Vat was found to be highly conserved and prevalent among a collection of urosepsis clinical isolates and was expressed at human core body temperature. Regulation of
vat
was demonstrated to be directly repressed by the global transcriptional regulator H-NS and upregulated by the downstream gene
vatX
(encoding a new MarR-type transcriptional regulator). Additionally, increased Vat-specific IgG titers were detected in plasma from corresponding urosepsis patients infected with
vat
-positive isolates. Hence, Vat is a highly conserved and tightly regulated urosepsis-associated virulence factor.
WrpA Is an Atypical Flavodoxin Family Protein under Regulatory Control of the Brucella abortus General Stress Response System
Authors: Herrou Julien , Czyż Daniel M. , Willett Jonathan W. , Kim Hye-Sook , Chhor Gekleng , Babnigg Gyorgy , Kim Youngchang , Crosson Sean 
Published: February 2016

ABSTRACTThe general stress response (GSR) system of the intracellular pathogenBrucella abortuscontrols the transcription of approximately 100 genes in response to a range of stress cues. The core genetic regulatory components of the GSR are required forB. abortussurvival under nonoptimal growth conditionsin vitroand for maintenance of chronic infection in anin vivomouse model. The functions of the majority of the genes in the GSR transcriptional regulon remain undefined.bab1_1070is among the most highly regulated genes in this regulon: its transcription is activated 20- to 30-fold by the GSR system under oxidative conditionsin vitro. We have solved crystal structures of Bab1_1070 and demonstrate that it forms a homotetrameric complex that resembles those of WrbA-type NADH:quinone oxidoreductases, which are members of the flavodoxin protein family. However,B. abortusWrbA-relatedprotein (WrpA) does not bind flavin cofactors with a high affinity and does not function as an NADH:quinone oxidoreductasein vitro. Soaking crystals with flavin mononucleotide (FMN) revealed a likely low-affinity binding site adjacent to the canonical WrbA flavin binding site. Deletion ofwrpA(ΔwrpA) does not compromise cell survival under acute oxidative stressin vitroor attenuate infection in cell-based or mouse models. However, a ΔwrpAstrain does elicit increased splenomegaly in a mouse model, suggesting that WrpA modulatesB. abortusinteraction with its mammalian host. Despite high structural homology with canonical WrbA proteins, we propose thatB. abortusWrpA represents a functionally distinct member of the diverse flavodoxin family.IMPORTANCEBrucella abortusis an etiological agent of brucellosis, which is among the most common zoonotic diseases worldwide. The general stress response (GSR) regulatory system ofB. abortuscontrols the transcription of approximately 100 genes and is required for maintenance of chronic infection in a murine model; the majority of GSR-regulated genes remain uncharacterized. We presentin vitroandin vivofunctional and structural analyses of WrpA, whose expression is strongly induced by GSR under oxidative conditions. Though WrpA is structurally related to NADH:quinone oxidoreductases, it does not bind redox cofactors in solution, nor does it exhibit oxidoreductase activityin vitro. However, WrpA does affect spleen inflammation in a murine infection model. Our data provide evidence that WrpA forms a new functional class of WrbA/flavodoxin family proteins.
Bibliometric analysis of the top-cited gastroenterology and hepatology articles
Authors: Azer Samy A , Azer Sarah 
Published: February 2016

ObjectiveTo identify the top-cited articles in gastroenterology and hepatology, and analyse their characteristics.MethodsTwo searches were conducted in the Science Citation Index Expanded database; a search of 69 journals under the category ‘Gastroenterology and Hepatology’ (list A) and a keyword search of all journals (list B). The search results were analysed and the inter-rater coefficient of agreement between evaluators was measured using Cohen κ.ResultsThe number of citations varied from 1049 to 2959 in list A and from 1929 to 5500 in list B. In both lists, the majority of articles were research papers. No significant correlations were found between the number of citations and the number of years since publication (R2=0.00992, p=0.473 and R2=0.00202, p=0.757, respectively). However, the mean number of citations of papers published before the year 2000 was lower than those published after 2000 (36.70±19.31 vs 106.03±39.22). No correlation was found between number of authors and the number of citations (R2=0.04352, p=0.130), but strong correlations were found between the number of institutes involved or number of countries and the number of citations (R2=0.275, p<0.001 and R2=0.16181, p=0.003, respectively). Females were under-represented in authorship (45 vs 254, p=0.004). Only 21 papers (of 54) in list A were supported by grants. No correlation was found between number of grants received and the number of citations (R2=0.02573, p=0.247). The inter-rater agreement between evaluators had a Cohen κ coefficient 0.76–0.84.ConclusionsTop-cited articles were not only published in highly ranked journals specialising in Gastroenterology and Hepatology but also in 14 journals not specialised in this field. The number of citations correlated with the number of institutes and the number of countries involved but not with the number of grants received or the number of authors. Females were under-represented in the authorship.
Social inequalities in prevalence of diagnosed and undiagnosed diabetes and impaired glucose regulation in participants in the Health Surveys for England series
Authors: Moody Alison , Cowley Giovanna , Ng Fat Linda , Mindell Jennifer S 
Published: February 2016

ObjectivesTo ascertain the extent of socioeconomic and health condition inequalities in people with diagnosed and undiagnosed diabetes and impaired glucose regulation (IGR) in random samples of the general population in England, as earlier diagnosis of diabetes and treatment of people with IGR can reduce adverse sequelae of diabetes. Various screening instruments were compared to identify IGR, in addition to undiagnosed diabetes.Design5, annual cross-sectional health examination surveys; data adjusted for complex survey design.SettingRandom selection of private homes across England, new sample annually 2009–2013.Participants5, nationally representative random samples of the general, free-living population: ≥1 adult interviewed in 24 254 of 36 889 eligible addresses selected. 18 399 adults had a valid glycated haemoglobin (HbA1c) measurement and answered the diabetes questions.Main outcome measuresDiagnosed diabetes, undiagnosed diabetes (HbA1c ≥48 mmol/mol), IGR (HbA1c 42–47 mmol/mol).ResultsOverall, 11% of the population had IGR, 2% undiagnosed and 6% diagnosed diabetes. Age-standardised prevalence was highest among Asian (19% (95% CI 16% to 23%), 3% (2% to 5%) and 12% (9% to 16%) respectively) and black participants (17% (13% to 21%), 2% (1% to 4%) and 14% (9% to 20%) respectively). These were also higher among people with lower income, less education, lower occupational class and greater deprivation. Education (OR 1.49 (95% CI 1.27 to 1.74) for no qualifications vs degree or higher) and income (1.35 (1.12 to 1.62) for lowest vs highest income quintile) remained significantly associated with IGR or undiagnosed diabetes on multivariate regression. The greatest odds of IGR or undiagnosed diabetes were with increasing age over 34 years (eg, OR 18.69 (11.53 to 30.28) aged 65–74 vs 16–24). Other significant associations were ethnic group (Asian (3.91 (3.02 to 5.05)), African-American (2.34 (1.62 to 3.38)) or ‘other’ (2.04 (1.07 to 3.88)) vs Caucasian); sex (OR 1.32(1.19 to 1.46) for men vs women); body mass index (3.54 (2.52 to 4.96) for morbidly obese vs not overweight); and waist circumference (2.00 (1.67 to 2.38) for very high vs low).ConclusionsSocial inequalities in hyperglycaemia exist, additional to well-known demographic and anthropometric risk factors for diabetes and IGR.
Introduction of a junior doctors' handbook: an essential guide for new doctors
Authors: Ross Daniella , Petrie Claire , Tully Vicki 
Published: February 2016

AbstractThe transition period for new junior doctors is a daunting and challenging time, as vast amounts of information specific to each hospital, ward, and job must be learnt while maintaining patient care standards.[1] In NHS Tayside, Scotland, tips and guidance for each job are informally handed over from previous junior doctors to the next, resulting in an unreliable and unsustainable handover of information. Time must then be spent by new doctors learning the intricacies and practicalities of their new job, rather than spending time focusing on patient care.Our aim was to improve this transition period for new junior doctors to NHS Tayside through the creation and implementation of a junior doctors' handbook, which would provide information and practical advice on day to day life as a junior doctor. We hoped to implement this project by August 2015 to coincide with the arrival of these new doctors to NHS Tayside. Through repeat PDSA cycles we created a sustainable and reliable junior doctors' handbook, containing a centralised hub of information for doctors that was accessible through our health board’s website. The junior doctors' handbook has been a highly beneficial resource that has been praised for its detailed information on all aspects of day to day life for doctors in NHS Tayside. Feedback also demonstrated that doctors felt the junior doctors' handbook had improved their efficiency. Our hope is that this project can continue to be developed within our hospital, but also to be used as an idea outside our health board to improve the transition period for new doctors on a wider scale.
Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy
Authors: Damy Thibaud , Maurer Mathew S , Rapezzi Claudio , Planté-Bordeneuve Violaine , Karayal Onur N , Mundayat Rajiv , Suhr Ole B , Kristen Arnt V 
Published: February 2016

BackgroundSigns of cardiac transthyretin (TTR) amyloidosis (ATTR) in patients with echocardiographic increase in interventricular septal thickness (IVST) are lacking.ObjectivesTo identify clinical and ECG/echocardiographic signs associated with increased IVST in ATTR.MethodsAnalysis of patients with baseline echocardiography in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry (N=1682). Patients were categorised into IVST classes according to the American Society of Echocardiography classification adapted to gender (ie, normal, mild, moderate, severe); then into two combined IVST classes (normal-mild and moderate-severe).Results425 patients were included: 336 with a TTR mutation (m-TTR) and 89 with wild-type TTR (WT-TTR). 72% were men. Median (25th, 75th centile) age was 62 (45, 72) years. Non-Val30Met and WT-TTR were frequent in moderate (41% and 35%) and severe (50% and 33%) IVST classes. Median IVST was 15 mm (14, 16) (moderate) and 20 mm (18, 22) (severe). In the combined moderate-severe class, 85% of patients were ≥55 years of age; 81% were men; 86% had blood pressure <140 mm Hg; and 77% had increased right ventricle thickness (≥7 mm). Up to 66% of patients had cardiac sparkling. Systolic dysfunction (left ventricular ejection fraction <50%), restrictive pattern and low voltage were less frequent, and observed in 49%, 18% and 33% of patients, respectively.ConclusionsIncreased IVST, especially in men ≥55 years with normal systolic blood pressure, increase in right ventricle free wall and valve thicknesses, and sparkling, should alert practitioners to the possibility of ATTR. Absence of restrictive pattern and low voltage should not rule out the suspicion.Trial registration number:NCT00628745 (clinicaltrials.gov).
Factors associated with a bad functional prognosis in early inflammatory back pain: results from the DESIR cohort
Authors: Lukas C , Dougados M , Combe B 
Published: February 2016

BackgroundSpondyloarthritis (SpA) is a heterogeneous disease with hardly predictable potential courses. We aimed at determining prognostic factors of bad functional outcome at 2 years in patients with early inflammatory back pain (IBP).MethodsData from patients included in the French multicentre devenir des spondylarthropathies indifférenciées récentes (DESIR) cohort, that is, suffering from IBP starting before 50 years of age and lasting for 3–36 months, were used. A bad functional outcome at 24 months was defined as an increase in bath ankylosing spondylitis functional index (BASFI), or BASFI at 2 years higher than the 75th centile in the cohort. Demographic, clinical, biological and radiological data collected at inclusion were compared in patients with bad functional outcome versus others, by χ2test, then by a multivariate logistic regression model with stepwise selection of relevant factors.Results513 patients (54.4% females, 72.2% fulfilling ASAS criteria) were assessed. Of those, 130 (25.3%) fulfilled the aforementioned criteria of a bad functional outcome (BASFI increase ≥4 units or ≥36 at 2 years). Multivariate analysis revealed that not fulfilling ASAS criteria, female sex, age >33 years, lower educational level, active smoking status and high disease activity according to bath ankylosing spondylitis disease activity index (BASDAI) at baseline were independently associated with a bad functional outcome at 24 months. Sensitivity analyses restricted to patients fulfilling ASAS criteria for SpA resulted in similar results.ConclusionWe observed, in a large prospective cohort of patients with early IBP, formerly described bad prognostic factors, especially a low educational level, an older age and a high disease activity at onset, and revealed that active smoking status and female sex were also independently associated with a poor outcome. Fulfilment of ASAS criteria, on the other hand, was predictive of a better outcome, most likely due to the more consensual management of a defined disease.
Regional scale hydrogeochemical mapping of the northern Yilgarn Craton, Western Australia: a new technology for exploration in arid Australia
Authors: Gray David J. , Noble Ryan R.P. , Reid Nathan , Sutton Gordon J. , Pirlo Mark C. 
Published: February 2016

The northern Yilgarn Craton, with an extensive mineral exploration history and relatively fresh and neutral groundwaters, was selected to test the utility of regional hydrogeochemical mapping in Australia. The assembled data of 2509 groundwater samples (generally at 4–8 km spacing) are relatively unbiased, allowing robust statistical analysis such as testing sample types (flowing v. ‘stagnant’), contamination, and lithological controls on groundwater characteristics. Lithological indicators were developed to map underlying bedrock through cover. Areas with discrepancies between groundwater results and previous geological mapping were identified. Where these are areas previously discounted as prospective for mineral commodities, they may now be re-considered on this basis. Even in well explored parts of this region, this study identified new areas which may have prospective rocks overlain with a thin (<50 m) veneer of granitic material. A large background data set was produced that has significant benefits for lithological discrimination, mineral exploration, guiding human and livestock drinking water supplies and environmental management (e.g. mine closure).
Groundwater chemistry can effectively map large-scale lithological changes in these semi-arid environments, and in turn can reduce uncertainly about the prospectivity of areas within the northern Yilgarn Craton. This should reduce the drilling and associated costs required to delineate a target. The methods and interpretation developed in this study will enhance mineral exploration into covered environments as much of the northern two thirds of Australia has similar groundwater environments. This methodology can be expanded into covered arid terrains worldwide. Additionally, this can be used as background to improve interpretation of other small scale studies. Improving the exploration potential of other more difficult regions of Australia will encourage industry exploration in Australia, and provide potential future economic gains.