bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a Single-Gene, Signature-Tag-Based Approach in Combination with Alanine Mutagenesis To Identify Listeriolysin O Residues Critical for theIn VivoSurvival of Listeria monocytogenes
Authors: Melton-Witt Jody A. , McKay Susannah L. , Portnoy Daniel A. 
Published: March 2012

ABSTRACTListeriolysin O (LLO) is a pore-forming toxin of the cholesterol-dependent cytolysin (CDC) family and a primary virulence factor of the intracellular pathogenListeria monocytogenes. LLO mediates rupture of phagosomal membranes, thereby releasing bacteria into the growth-permissive host cell cytosol. Several unique features of LLO allow its activity to be precisely regulated in order to facilitate phagosomal escape, intracellular growth, and cell-to-cell spread. To improve our understanding of the multifaceted contribution of LLO to the pathogenesis ofL. monocytogenes, we developed a screen that combined saturation mutagenesis and signature tags, termedinvivoanalysis bysaturation mutagenesis andsignature tags (IVASS). We generated a library of LLO mutant strains, each harboring a single amino acid substitution and a signature tag, by using the previously described pPL2 integration vector. The signature tags acted as molecular barcodes, enabling high-throughput, parallel analysis of 40 mutants in a single animal and identification of attenuated mutants by negative selection. Using the IVASS technique we were able to screen over 90% of the 505 amino acids present in LLO and identified 60 attenuated mutants. Of these, 39 LLO residues were previously uncharacterized and potentially revealed novel functions of the toxin during infection. The mutants that were subsequently analyzedin vivoeach conferred a 2- to 4-orders of magnitude loss in virulence compared to wild type, thereby validating the screening methods. Phenotypic analysis of the LLO mutant library using commonin vitrotechniques suggested that the functional contributions of some residues could only have been revealed throughin vivoanalysis.
L-Ficolin and Capsular Polysaccharide-Specific IgG in Cord Serum Contribute Synergistically to Opsonophagocytic Killing of Serotype III and V Group B Streptococci
Authors: Fujieda Mioko , Aoyagi Youko , Matsubara Kousaku , Takeuchi Yasuhito , Fujimaki Wakae , Matsushita Misao , Bohnsack John F. , Takahashi Shinji 
Published: March 2012

ABSTRACT

Group B streptococci (GBS;
Streptococcus agalactiae
) are the most common cause of neonatal sepsis and meningitis. Serotype-specific IgG antibody is known to protect neonates against GBS infections by promoting opsonophagocytosis. The L-ficolin-mediated lectin pathway of the complement is also a potential mechanism for opsonization of GBS, because L-ficolin activates the complement after binding to serotype Ib, III, V, VI, and VIII GBS. In the present study, we investigated how L-ficolin and serotype-specific IgG in cord sera contribute to opsonophagocytic killing of GBS. Neither L-ficolin nor serotype-specific IgG concentrations correlated with C3b deposition on serotype Ib and VI GBS, suggesting L-ficolin- and serotype-specific IgG-independent mechanisms of complement activation. The percentage of serotype VIII GBS killed was high regardless of the concentration of L-ficolin and IgG. In contrast, L-ficolin and serotype-specific IgG can each initiate C3b deposition on serotype III and V GBS and promote phagocytosis by polymorphonuclear leukocytes, but L-ficolin and serotype-specific IgG together promote opsonophagocytic killing to a greater extent than does either alone
in vitro
. This synergy was observed when serotype III-specific IgG concentrations were between 1 and 6 μg/ml and when serotype V-specific IgG concentrations were between 2 and 5 μg/ml. Concentrations of serotype III-specific IgG in cord blood above 7 μg/ml are considered protective for neonates colonized with GBS, but most neonates with IgG levels of less than 7 μg/ml do not develop GBS infections. The data presented here suggest that L-ficolin enhances opsonophagocytosis of serotype III and V GBS when serotype-specific IgG alone is suboptimal for protection.
IbeA and OmpA of Escherichia coli K1 Exploit Rac1 Activation for Invasion of Human Brain Microvascular Endothelial Cells
Authors: Maruvada Ravi , Kim Kwang Sik 
Published: March 2012

ABSTRACT

Meningitis-causing
Escherichia coli
K1 internalization of the blood-brain barrier is required for penetration into the brain, but the host-microbial interactions involved in
E. coli
entry of the blood-brain barrier remain incompletely understood. We show here that a meningitis-causing
E. coli
K1 strain RS218 activates Rac1 (GTP-Rac1) of human brain microvascular endothelial cells (HBMEC) in a time-dependent manner. Both activation and bacterial invasion were significantly inhibited in the presence of a Rac1 inhibitor. We further showed that the guanine nucleotide exchange factor Vav2, not β-Pix, was involved in
E. coli
K1-mediated Rac1 activation. Since activated STAT3 is known to bind GTP-Rac1, the relationship between STAT3 and Rac1 was examined in
E. coli
K1 invasion of HBMEC. Downregulation of STAT3 resulted in significantly decreased
E. coli
invasion compared to control HBMEC, as well as a corresponding decrease in GTP-Rac1, suggesting that Rac1 activation in response to
E. coli
is under the control of STAT3. More importantly, two
E. coli
determinants contributing to HBMEC invasion, IbeA and OmpA, were shown to affect both Rac1 activation and their association with STAT3. These findings demonstrate for the first time that specific
E. coli
determinants regulate a novel mechanism of STAT3 cross talk with Rac1 in
E. coli
K1 invasion of HBMEC.
Risk of developing disability in pre and post-multidrug therapy treatment among multibacillary leprosy: Agra MB Cohort study
Authors: Kumar Anil , Girdhar Anita , Girdhar Bhavneswar Kumar 
Published: March 2012

ObjectivesIf leprosy is a public health problem, it is due to the disabilities it causes. Surprisingly little is known about the risk of disabilities. Even now, mainly cross-sectional studies report disability prevalence. The present study aims to report the risk of disability in pre and post-WHO multidrug therapy (MDT) in multibacillary leprosy patients and to assess the extent of the incidence of disability.MethodsThe study design is prospective and the setting is an institutional field area. Patients were detected during 2001–6 field surveys. Of the 289 multibacillary patients, 146 completed the study. Both sexes were involved. The primary outcome planned was to study cure of disease, relapses and disability in patients receiving MDT. The secondary outcome was to measure reaction and default. Assessment was done clinically. Data have been analysed using SPSS software, logistic, survival analysis was performed and the χ2test of significance was used.ResultsAn important risk factor was found to be three or more nerves involved with odds of 3.73 (1.24–11.2), and delay in treatment; 2.27 (1.04–4.96) at the pre-MDT stage and three or more nerves involved with odds of 2.81 (1.0–7.9) at the post-MDT stage. The incidence of disability was found to be 2.74/100 person-years; 2.69 in the MDT arm and 2.84 in defaulters, with slightly higher disability among early defaulters (3.08) than among late defaulters (2.30). The study suggests that the incidence of disability could be slightly higher if treatment is not completed.ConclusionEarly treatment for leprosy is a must for reducing the risk of disability, and treatment delay would increase the risk of disability. It is important to note that the incidence of disability between defaulters and those completing treatment was not found to be significantly different.
Elderly falls: a national survey of UK ambulance services
Authors: Darnell Gareth , Mason Suzanne M , Snooks Helen 
Published: March 2012

ObjectiveTo provide a detailed description of the current UK ambulance service provision for older people who fall.MethodNational survey of UK ambulance services.Results11/13 Ambulance services (84.6%) participated in this national survey.ConclusionThis survey has highlighted the need for robust evidence to inform policy, service and practice development to improve the care of this vulnerable population.
Contraceptive efficacy and tolerability of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen: an open-label, multicentre, randomised, controlled study
Authors: Klipping Christine , Duijkers Ingrid , Fortier Michel P , Marr Joachim , Trummer Dietmar , Elliesen Jörg 
Published: March 2012

BackgroundThe contraceptive efficacy and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg to extend the menstrual cycle and enable management of intracyclic (breakthrough) bleeding (flexibleMIB) was investigated and the bleeding pattern compared with a conventional 28-day regimen and a fixed extended 124-day regimen.Study designThis Phase III, 2-year, multicentre, open-label study randomly (4:1:1) allocated women (aged 18–35 years) to the following regimens: flexibleMIB(24–120 days' active hormonal intake with 4-day tablet-free intervals); conventional (24 days' active hormonal intake followed by a 4-day hormone-free interval); or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval). Primary outcomes included the number of bleeding/spotting days during Year 1 (all regimens) and the number of observed unintended pregnancies over 2 years (flexibleMIBonly).ResultsResults were analysed in 1067 women (full analysis set). The mean number of bleeding/spotting days was lower with the flexibleMIBvs the conventional regimen [41.0±29.1 (95% CI 38.8–43.3) vs 65.8±27.0 (95% CI 62.2–69.4) days,p<0.0001; treatment difference −24.8 (95% CI −29.2 to −20.3) days]. The corresponding value for the fixed extended regimen was 60.9±51.1 (95% CI 53.9–67.9) days. The Pearl Index for the flexibleMIBregimen was 0.64 (95% CI 0.28–1.26). All regimens had comparable tolerability profiles.ConclusionsEE 20 μg/DRSP 3 mg administered as a flexible extended regimen with MIB is effective, well tolerated and is associated with statistically significantly fewer bleeding/spotting days and fewer withdrawal bleeding episodes vs EE/DRSP in a conventional 28-day regimen. The flexibleMIBalso provided statistically significantly fewer spotting days vs EE/DRSP in a fixed extended 124-day regimen (post hocevaluation). The flexibleMIBregimen allows women to extend their menstrual cycle and manage their intracyclic (breakthrough) bleeding.
Long-term tolerability of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study
Authors: Klipping Christine , Duijkers Ingrid , Fortier Michel P , Marr Joachim , Trummer Dietmar , Elliesen Jörg 
Published: March 2012

BackgroundThis study was designed to assess the long-term safety and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 μg/drospirenone (DRSP) 3 mg, which allows management of intracyclic (breakthrough) bleeding [flexible management of intracyclic (breakthrough) bleeding (MIB)], in comparison to conventional 28-day and fixed extended regimens.Study designIn this Phase III, multicentre, open-label study, women (aged 18–35 years) were randomised to EE/DRSP in the following regimens: flexibleMIB(24–120 days' active hormonal intake followed by a 4-day tablet-free interval), conventional 28-day (24 days' active hormonal intake followed by a 4-day hormone-free interval) or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) during a 1-year comparative phase. Thereafter, women entered a 1-year safety extension phase in which the majority received the flexibleMIBregimen. Safety/tolerability outcomes were measured over 2 years. A separate analysis of certain safety parameters (endometrial, hormonal, lipid, haemostatic and metabolic variables) was conducted at two of the study centres.ResultsResults were analysed in 1067 and 783 women in the comparative and safety extension phases. Overall, 56.3% of women experienced ≥1 adverse event (AE) in the safety extension phase. Serious AEs occurred in 3.0%, 1.4% and 3.3% of women receiving the flexibleMIB, conventional and fixed extended regimens, respectively. No unexpected endometrial, hormonal, lipid, haemostatic or metabolic findings occurred with any of the three regimens.ConclusionsEE/DRSP in a flexible extended regimen with management of intracyclic (breakthrough) bleeding is well-tolerated and, when administered for up to 2 years, has a good safety profile comparable to other estrogen/progestogen oral contraceptives.
Understanding age and technology experience differences in use of prior knowledge for everyday technology interactions
Authors: O'brien Marita A. , Rogers Wendy A. , Fisk Arthur D. 
Published: March 2012

Technology designers must understand relevant prior knowledge in a target user population to facilitate adoption and effective use. To assess prior knowledge used in naturalistic settings, we systematically collected information about technologies used over 10-day periods from older adults with high and low technology experience and younger adults. Technology repertoires for younger adults and high technology older adults were similar; differences reflected typically different needs for kitchen and health care technologies between the age groups. Technology repertoires for low-technology older adults showed substantial technology usage in many categories. Lower usage compared to high-tech older adults for each category was limited primarily to PC and Internet technologies. Experience differences suggest preferences among low-technology older adults for basic technology usage and for working with people rather than technologies.
Participants in all groups were generally successful using their everyday technologies to achieve their goals. Prior knowledge was the most common attribution for success, but external information was also commonly referenced. Relevant prior knowledge included technical, functional, strategy, and self knowledge. High tech older adults did not report more problems than younger adults, but they did attribute more problems to insufficient prior knowledge. Younger adults attributed more problems to interference from prior knowledge. Low-tech older adults reported fewer problems, typically attributing them to insufficient prior knowledge or product/system faults. We discuss implications for further research and design improvements to increase everyday technology success and adoption for high-tech and low-tech older adults.
The impact of optional type information on jit compilation of dynamically typed languages
Authors: Chang Mason , Mathiske Bernd , Smith Edwin , Chaudhuri Avik , Gal Andreas , Bebenita Michael , Wimmer Christian , Franz Michael 
Published: March 2012

Optionally typed languages enable direct performance comparisons between untyped and type annotated source code. We present a comprehensive performance evaluation of two different JIT compilers in the context of ActionScript, a production-quality optionally typed language. One JIT compiler is optimized for quick compilation rather than JIT compiled code performance. The second JIT compiler is a more aggressively optimizing compiler, performing both high-level and low-level optimizations.
We evaluate both JIT compilers directly on the same benchmark suite, measuring their performance changes across fully typed, partially typed, and untyped code. Such evaluations are especially relevant to dynamically typed languages such as JavaScript, which are currently evaluating the idea of adding optional type annotations. We demonstrate that low-level optimizations rarely accelerate the program enough to pay back the investment into performing them in an optionally typed language. Our experiments and data demonstrate that high-level optimizations are required to improve performance by any significant amount.
HappyJIT
Authors: Homescu Andrei , Şuhan Alex 
Published: March 2012

Current websites are a combination of server-generated dynamic content with client-side interactive programs. Dynamically - typed languages have gained a lot of ground in both of these domains. The growth of Web 2.0 has introduced a myriad of websites which contain personalized content, which is specific to the user. PHP or Python programs generate the actual HTML page after querying a database and processing the results, which are then presented by the browser. It is becoming more and more vital to accelerate the execution of these programs, as this is a significant part of the total time needed to present the page to the user.
This paper presents a novel interpreter for the PHP language written in RPython, which the PyPy translator then translates into C. The translator integrates into the interpreter a tracing just-in-time compiler which optimizes the hottest loops in the interpreted programs. We also describe a data model that supports all the data types in the PHP language, such as references and iterators. We evaluate the performance of this interpreter, showing that speedups up to a factor of 8 are observed using this approach.
Explicit use-case representation in object-oriented programming languages
Authors: Hirschfeld Robert , Perscheid Michael , Haupt Michael 
Published: March 2012

Use-cases are considered an integral part of most contemporary development processes since they describe a software system's expected behavior from the perspective of its prospective users. However, the presence of and traceability to use-cases is increasingly lost in later more code-centric development activities. Use-cases, being well-encapsulated at the level of requirements descriptions, eventually lead to crosscutting concerns in system design and source code. Tracing which parts of the system contribute to which use-cases is therefore hard and so limits understandability.
In this paper, we propose an approach to making use-cases first-class entities in both the programming language and the runtime environment. Having use-cases present in the code and the running system will allow developers, maintainers, and operators to easily associate their units of work with what matters to the users. We suggest the combination of use-cases, acceptance tests, and dynamic analysis to automatically associate source code with use-cases. We present UseCasePy, an implementation of our approach to use-case-centered development in Python, and its application to the Django Web framework.
Pulmonary Arterial Hypertension in Patients Treated by Dasatinib
Authors: Montani David , Bergot Emmanuel , Günther Sven , Savale Laurent , Bergeron Anne , Bourdin Arnaud , Bouvaist Helene , Canuet Matthieu , Pison Christophe , Macro Margareth , Poubeau Patrice , Girerd Barbara , Natali Delphine , Guignabert Christophe , Perros Frédéric , O'Callaghan Dermot S. , Jaïs Xavier , Tubert-Bitter Pascale , Zalcman Gérard , Sitbon Olivier , Simonneau Gérald , Humbert Marc 
Published: March 2012

Background—
The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.

Methods and Results—
This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.

Conclusions—
Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
Application of Geographic Modeling Techniques to Quantify Spatial Access to Health Services Before and After an Acute Cardiac Event
Authors: Clark Robyn A. , Coffee Neil , Turner Dorothy , Eckert Kerena A. , van Gaans Deborah , Wilkinson David , Stewart Simon , Tonkin Andrew M. 
Published: March 2012

Background
Access to cardiac services is essential for appropriate implementation of evidence-based therapies to improve outcomes. The Cardiac Accessibility and Remoteness Index for Australia (Cardiac ARIA) aimed to derive an objective, geographic measure reflecting access to cardiac services.

Methods and Results
An expert panel defined an evidence-based clinical pathway. Using Geographic Information Systems (GIS), the team developed a numeric/alphabetic index at 2 points along the continuum of care. The acute category (numeric) measured the time from the emergency call to arrival at an appropriate medical facility via road ambulance. The aftercare category (alphabetic) measured access to 4 basic services (family doctor, pharmacy, cardiac rehabilitation, and pathology services) when a patient returned to his or her community. The numeric index ranged from 1 (access to principal referral center with cardiac catheterization service ≤1 hour) to 8 (no ambulance service, >3 hours to medical facility, air transport required). The alphabetic index ranged from A (all 4 services available within a 1-hour drive-time) to E (no services available within 1 hour). The panel found that 13.9 million Australians (71%) resided within Cardiac ARIA 1A locations (hospital with cardiac catheterization laboratory and all aftercare within 1 hour). Those outside Cardiac 1A were overrepresented by people >65 years of age (32%) and indigenous people (60%).

Conclusions
The Cardiac ARIA index demonstrated substantial inequity in access to cardiac services in Australia. This methodology can be used to inform cardiology health service planning and could be applied to other common disease states within other regions of the world.