bluuebunny/crossref_metadata_2025 huggingface dataset:
Divalent Metals and pH Alter Raltegravir Disposition
In Vitro
Authors: Moss Darren M. , Siccardi Marco , Murphy Matthew , Piperakis Michael M. , Khoo Saye H. , Back David J. , Owen Andrew
Published: March 2012

Raltegravir shows marked pharmacokinetic variability in patients, with gastrointestinal pH and divalent-metal binding being potential factors. We investigated raltegravir solubility, lipophilicity, pK
a
, and permeativity
in vitro
to elucidate known interactions with omeprazole, antacids, and food, all of which increase gastric pH. Solubility of raltegravir was determined at pH 1 to 8. Lipophilicity of raltegravir was determined using octanol-water partition. Raltegravir pK
a
was determined using UV spectroscopy. The effects of pH, metal salts, and omeprazole on the cellular permeativity of raltegravir were determined using Caco-2 monolayers. Cellular accumulation studies were used to determine the effect of interplay between pH and ABCB1 transport on raltegravir accumulation. Samples were analyzed using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) or scintillation counting. Raltegravir at 10 mM was partly insoluble at pH 6.6 and below. Raltegravir lipophilicity was pH dependent and was reduced as pH was increased from 5 to 9. The pK
a
of raltegravir was 6.7. Raltegravir cellular permeativity was heavily influenced by changes in extracellular pH, where apical-to-basolateral permeativity was reduced 9-fold (
P
< 0.05) when apical pH was increased from 5 to 8.5. Raltegravir cellular permeativity was also reduced in the presence of magnesium and calcium. Omeprazole did not alter raltegravir cellular permeativity. Cellular accumulation of raltegravir was increased independently by inhibiting ABCB1 and by lowering extracellular pH from pH 8 to 5. Gastrointestinal pH and polyvalent metals can potentially alter the pharmacokinetic properties of raltegravir, and these data provide an explanation for the variability in raltegravir exposure in patients. The evaluation of how divalent-metal-containing products, such as multivitamins, that do not affect gastric pH alter raltegravir pharmacokinetics in patients is now justified.
Molecular Characterization of Multidrug-Resistant Mycobacterium tuberculosis Isolated in Nepal
Authors: Poudel Ajay , Nakajima Chie , Fukushima Yukari , Suzuki Haruka , Pandey Basu Dev , Maharjan Bhagwan , Suzuki Yasuhiko
Published: March 2012

Despite the fact that Nepal is one of the first countries globally to introduce multidrug-resistant tuberculosis (MDR-TB) case management, the number of MDR-TB cases is continuing to rise in Nepal. Rapid molecular tests applicable in this setting to identify resistant organisms would be an effective tool in reversing this trend. To develop such tools, information about the frequency and distribution of mutations that are associated with phenotypic drug resistance inMycobacterium tuberculosisis required. In the present study, we investigated the prevalence of mutations inrpoBandkatGgenes and theinhApromoter region in 158M. tuberculosisisolates (109 phenotypically MDR and 49 non-MDR isolates collected in Nepal) by DNA sequencing. Mutations affecting the 81-bp rifampin (RIF) resistance-determining region (RRDR) ofrpoBwere identified in 106 of 109 (97.3%) RIF-resistant isolates. Codons 531, 526, and 516 were the most commonly affected, at percentages of 58.7, 15.6, and 15.6%, respectively. Of 113 isoniazid (INH)-resistant isolates, 99 (87.6%) had mutations in thekatGgene, with Ser315Thr being the most prevalent (81.4%) substitution. Mutations in theinhApromoter region were detected in 14 (12.4%) INH-resistant isolates. The results from this study provide an overview of the current situation of RIF and INH resistance inM. tuberculosisin Nepal and can serve as a basis for developing or improving rapid molecular tests to monitor drug-resistant strains in this country.
The Type II Secretion System and Its Ubiquitous Lipoprotein Substrate, SslE, Are Required for Biofilm Formation and Virulence of Enteropathogenic Escherichia coli
Authors: Baldi Deborah L. , Higginson Ellen E. , Hocking Dianna M. , Praszkier Judyta , Cavaliere Rosalia , James Catherine E. , Bennett-Wood Vicki , Azzopardi Kristy I. , Turnbull Lynne , Lithgow Trevor , Robins-Browne Roy M. , Whitchurch Cynthia B. , Tauschek Marija
Published: March 2012

Enteropathogenic
Escherichia coli
(EPEC) is a major cause of diarrhea in infants in developing countries. We have identified a functional type II secretion system (T2SS) in EPEC that is homologous to the pathway responsible for the secretion of heat-labile enterotoxin by enterotoxigenic
E. coli
. The wild-type EPEC T2SS was able to secrete a heat-labile enterotoxin reporter, but an isogenic T2SS mutant could not. We showed that the major substrate of the T2SS in EPEC is SslE, an outer membrane lipoprotein (formerly known as YghJ), and that a functional T2SS is essential for biofilm formation by EPEC. T2SS and SslE mutants were arrested at the microcolony stage of biofilm formation, suggesting that the T2SS is involved in the development of mature biofilms and that SslE is a dominant effector of biofilm development. Moreover, the T2SS was required for virulence, as infection of rabbits with a rabbit-specific EPEC strain carrying a mutation in either the T2SS or SslE resulted in significantly reduced intestinal colonization and milder disease.
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

Listeriolysin 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

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

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

Objectives

If 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.

Methods

The 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.

Results

An 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.

Conclusion

Early 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

Objective

To provide a detailed description of the current UK ambulance service provision for older people who fall.

Method

National survey of UK ambulance services.

Results

11/13 Ambulance services (84.6%) participated in this national survey.

Conclusion

This 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

Background

The 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 design

This 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).

Results

Results 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.

Conclusions

EE 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

Background

This 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 design

In 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.

Results

Results 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.

Conclusions

EE/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.
HALF-LIVES OF BISMUTH DEFORMED ISOTOPES IN MULTIPLE APPROXIMATION BASIS
Authors: JAVADIMANESH E. , HASSANABADI H. , RAJABI A. A. , RAHIMOV H. , ZARRINKAMAR S.
Published: March 2012

We intend to study the half-lives of Bismuth isotopes via the alpha decay process. To go through the problem, we consider a potential model in which an angle-dependence is considered. Our results reveal that taking into account the multipole approximations for both parent and daughter nuclei will improve the results.
NUMERICAL INVESTIGATION OF PULSATILE FLOW IN AN S-TYPE BYPASS GRAFT
Authors: JIANG WENTAO , ZHENG TINGHUI , CHEN JUNKAI , DENG XIAOYAN , FAN YUBO
Published: March 2012

Intimal hyperplasia developed at the end-to-side anastomosis of artery bypass is closely related to unphysiological hemodynamics. The helical flow as a normal physiological phenomenon in arteries is beneficial to endothelial damage repair. To deeply understand the physiological flow properties in a S-type bypass (StB) graft, four end-to-side bypass models including 30°, 45°, 60° conventional bypasses and a 45° StB were compared numerically under physiological pulsatile flow. The results showed that strong helical flow was observed at the distal anastomosis of StB. The distribution of hemodynamic parameters such as helicity, average wall shear stress and oscillating shear index, etc. were significantly improved at the S-type anastomosis as compared with those of three conventional models. The area-averaged normalized helicity in StB reached maxima at the moments of maximum flow rate and systolic deceleration. The hemodynamic performance in a 45° StB was improved as compared with a 30° conventional model. It is concluded that large StB anastomosis angle can be taken to achieve good hemodynamic performance while much smaller anastomosis angle has to be adopted for conventional bypass. As such, a S-type anastomosis should be a feasible choice of clinical artery bypass grafting due to its significant improvement in hemodynamic performance.
REMOVABLE SETS FOR HÖLDER CONTINUOUS p(x)-HARMONIC FUNCTIONS
Authors: LYAGHFOURI A.
Published: March 2012

We establish that a closed set E is removable for C0,αHölder continuous p(x)-harmonic functions in a bounded open domain Ω of ℝn, n ≥ 2, provided that for each compact subset K of E, the (n - pK+ α(pK- 1))-Hausdorff measure of K is zero, where pK= maxx∈Kp(x).
ASYMPTOTICS OF ORTHOGONAL POLYNOMIALS VIA RECURRENCE RELATIONS
Authors: WANG X.-S. , WONG R.
Published: March 2012

We use the Legendre polynomials and the Hermite polynomials as two examples to illustrate a simple and systematic technique on deriving asymptotic formulas for orthogonal polynomials via recurrence relations. Another application of this technique is to provide a solution to a problem recently raised by M. E. H. Ismail.
Verified Cryptographic Implementations for TLS
Authors: Bhargavan Karthikeyan , Fournet Cédric , Corin Ricardo , Zălinescu Eugen
Published: March 2012

We narrow the gap between concrete implementations of cryptographic protocols and their verified models. We develop and verify a small functional implementation of the Transport Layer Security protocol (TLS 1.0). We make use of the same executable code for interoperability testing against mainstream implementations for automated symbolic cryptographic verification and automated computational cryptographic verification. We rely on a combination of recent tools and also develop a new tool for extracting computational models from executable code. We obtain strong security guarantees for TLS as used in typical deployments.
Anatree
Authors: Reams Charles
Published: March 2012

Natural language is a rich source of constraint satisfaction problems (CSPs), with a uniquely structured solution domain. We describe a number of approaches to satisfying the particular case of unordered letter-level constraints, including anagrams, but also relevant to typographical error correction, password security and word puzzles among other fields. We define the
anatree
, a data structure that can solve many such problems in constant time with respect to the size of the lexicon. The structure represents the lexicon of a language in a format somewhat analogous to a binary decision diagram (BDD) and, as with BDDs, construction heuristics allow the real average-case performance to vastly exceed the theoretical worst case. We compare anatrees and their alternatives empirically, explore the behavior of the construction heuristics, and characterize the tasks for which each is best suited.
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.
An interpreter for server-side hop
Authors: Bernard Serpette P. , Manuel Serrano
Published: March 2012

HOP is a Scheme-based multi-tier programming language for the Web. The client-side of a program is compiled to JavaScript, while the server-side is executed by a mix of natively compiled code and interpreted code. At the time where HOP programs were basic scripts, the performance of the server-side interpreter was not a concern; an inefficient interpreter was acceptable. As HOP expanded, HOP programs got larger and more complex. A more efficient interpreter was necessary. This new interpreter is described in this paper. It is compact, its whole implementation counting no more than 2.5 KLOC. It is more than twice faster than the old interpreter and consumes less than a third of its memory. Although it cannot compete with static or JIT native compilers, our experimental results show that it is amongst the fastest interpreters for dynamic languages.
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.
Bootstrapping a self-hosted research virtual machine for JavaScript
Authors: Chevalier-Boisvert Maxime , Lavoie Erick , Feeley Marc , Dufour Bruno
Published: March 2012

JavaScript is one of the most widely used dynamic languages. The performance of existing JavaScript VMs, however, is lower than that of VMs for static languages. There is a need for a research VM to easily explore new implementation approaches. This paper presents the Tachyon JavaScript VM which was designed to be flexible and to allow experimenting with new approaches for the execution of JavaScript. The Tachyon VM is itself implemented in JavaScript and currently supports a subset of the full language that is sufficient to bootstrap itself. The paper discusses the architecture of the system and in particular the bootstrapping of a self-hosted VM. Preliminary performance results indicate that our VM, with few optimizations, can already execute code faster than a commercial JavaScript interpreter on some benchmarks.
Places
Authors: Tew Kevin , Swaine James , Flatt Matthew , Findler Robert Bruce , pdinda@northwestern.edu Peter Dinda
Published: March 2012

Places
bring new support for message-passing parallelism to Racket. This paper gives an overview of the programming model and how we had to modify our existing, sequential runtime-system to support places. We show that the freedom to design the programming model helped us to make the implementation tractable; specifically, we avoided the conventional pain of adding just the right amount of locking to a big, legacy runtime system. The paper presents an evaluation of the design that includes both a real-world application and standard parallel benchmarks.
Differential Proteome Profiling Using iTRAQ in Microalbuminuric and Normoalbuminuric Type 2 Diabetic Patients
Authors: Jin Jonghwa , Ku Yun Hyi , Kim Yikwon , Kim Yeonjung , Kim Kyunggon , Lee Ji Yoon , Cho Young Min , Lee Hong Kyu , Park Kyong Soo , Kim Youngsoo
Published: March 2012

Diabetic nephropathy (DN) is a long-term complication of diabetes mellitus that leads to end-stage renal disease. Microalbuminuria is used for the early detection of diabetic renal damage, but such levels do not reflect the state of incipient DN precisely in type 2 diabetic patients because microalbuminuria develops in other diseases, necessitating more accurate biomarkers that detect incipient DN. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify urinary proteins that were differentially excreted in normoalbuminuric and microalbuminuric patients with type 2 diabetes where 710 and 196 proteins were identified and quantified, respectively. Some candidates were confirmed by 2-DE analysis, or validated by Western blot and multiple reaction monitoring (MRM). Specifically, some differentially expressed proteins were verified by MRM in urine from normoalbuminuric and microalbuminuric patients with type 2 diabetes, wherein alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, and prostate stem cell antigen had excellent AUC values (0.849, 0.873, and 0.825, resp.). Moreover, we performed a multiplex assay using these biomarker candidates, resulting in a merged AUC value of 0.921. Although the differentially expressed proteins in this iTRAQ study require further validation in larger and categorized sample groups, they constitute baseline data on preliminary biomarker candidates that can be used to discover novel biomarkers for incipient DN.
Using a Herd Profile to Determine Age-Specific Prevalence of Bovine Leukemia Virus in Michigan Dairy Herds
Authors: Erskine Ronald J. , Bartlett Paul C. , Byrem Todd M. , Render Chelsea L. , Febvay Catherine , Houseman Jessica T.
Published: March 2012

Enzootic bovine leukosis is a contagious disease of cattle caused by the retrovirus, bovine leukemia virus (BLV) and is the most common cause of malignant neoplasm in cattle. In order to facilitate surveillance of this disease in dairy herds, we developed a method to combine ELISA of milk collected during routine production testing with a prescribed sampling of cows that is independent of the proportion of cows within each lactation. In 113 Michigan dairy herds, milk samples from ten cows in each of the 1st, 2nd, 3rd, and ≥4th lactations were analyzed for anti-Bovine Leukemia Virus (BLV) antibodies by milk ELISA. For each herd, a BLV herd profile (BHP) was calculated as the simple average of the percent of BLV-positive cows within each of the four lactation groups. The mean BHP for all herds was 32.8%, with means of 18.5, 28.8, 39.2, and 44.8% of 1st, 2nd, 3rd, and ≥4th lactation animals infected, respectively. In eight herds, we determined the correlation between the BHP, and true herd prevalence by testing the entire lactating herd (r=0.988,  P<0.0001). The BHP allows discrimination of lactation-specific BLV prevalence within a dairy herd, to help identify risk factors and management plans that may be important in transmission of BLV.
Cerebral Subdural Hematoma Following Spinal Anesthesia: Report of Two Cases
Authors: Moradi Mehrdad , Shami Shoaleh , Farhadifar Fariba , Nesseri Karim
Published: March 2012

Postdural puncture headache and cerebral subdural hematoma are among complications of spinal anesthesia with some common characteristics; however misdiagnosis of these two could result in a catastrophic outcome or prevent unwanted results by urgent interventions. With the purpose of increasing awareness of such complications and a speedy diagnosis, we report two cases of postspinal anesthesia headache that was timely diagnosed as cerebral subdural hematoma and prevented the likelihood of a disastrous outcome.
Dramatic Clinical Response of Relapsed Metastatic Extramammary Paget’s Disease to Trastuzumab Monotherapy
Authors: Wakabayashi S. , Togawa Y. , Yoneyama K. , Suehiro K. , Kambe N. , Matsue H.
Published: March 2012

We report the first case of 68-year-old Japanese woman with metastatic HER2-positive extramammary Paget’s disease that showed the validity of trastuzumab monotherapy. We administered trastuzumab at a loading dose of 8 mg/kg i.v., followed by a 6 mg/kg maintenance dose every three weeks according to a protocol for HER2-positive metastatic breast cancers and a near-complete response was achieved after the tenth infusion. The patient experienced a moderate headache and flushing during the first infusion, but had no advanced effects during subsequent infusions with ibuprofen and d-chlorpheniramine maleate. Given the dramatic response, the patient has had 17 infusions of trastuzumab with no disease progression. Thus, trastuzumab has few side effects and is well tolerated for elderly patients. It may become a new choice of the adjubant therapy of this disease.
Upper Gastrointestinal Endoscopy Detection of Synchronous Multiple Primary Cancers in Esophagus and Stomach: Single Center Experience from China
Authors: Wang Rui , Wang Mo-Jin , Yang Jin-Lin , Tang Cheng-Wei
Published: March 2012

The present study was undertaken to clarify the prevalence and clinicopathological features of synchronous multiple primary cancers (SMPCs) under upper gastrointestinal endoscopic examination. We enrolled 45,032 consecutive patients who underwent upper gastrointestinal endoscopic examination for digestive disease from January 2006 to December 2007 in our hospital and analyzed the clinicopathological features of SMPCs in esophagus and stomach. SMPCs are defined as two or over two different cancerous lesions developing in the same or other organs within 6 months. SMPCs were identified in 46 patients (0.1%). The gender ratio was 5.6 : 1 (male/female) and the mean age was 59.4 years. Synchronous esophageal and gastric cancers were the most frequent, being seen in 32 patients (0.07%). The most common histological types of SMPCs were squamous cell carcinoma in esophagus and adenocarcinoma in stomach, respectively. There were 27 (59%) SMPCs patients who had the history of simultaneous exposure to tobacco smoking and alcohol drinking. Additionally, 32 (78%) esophageal squamous cell cancers were associated with tobacco use. And 23 adenocarcinomas of the stomach were associated withHelicobacter pyloriinfection.
Hyperandrogenism Does Not Influence Metabolic Parameters in Adolescent Girls with PCOS
Authors: Forrester-Dumont Kim , Galescu Ovidiu , Kolesnikov Andrey , Raissouni Nouhad , Bhangoo Amrit , Ten Svetlana , Suss Amy
Published: March 2012

Background.Underlying insulin resistance and/or obesity has clearly been implicated in the development of metabolic syndrome in adolescents and young adults with polycystic ovarian syndrome (PCOS). It is not clear however what role hyperandrogenism has on the development of metabolic syndrome or its role on those metabolic parameters associated with metabolic syndrome.Methods.We studied 107 adolescent girls; 54 had PCOS according to NIH criteria. Data was obtained for systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), total testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, fasting lipid profile, and glucose. The PCOS group was divided initially into subgroups according to BMI (kg/m2), then based on T (ng/dL) levels as follows: High Testosterone PCOS (HT), Intermediate Testosterone PCOS (IT), Obese and Normal Testosterone (ONT), and lean and normal T (Control, C).t-test analysis was performed in between all the groups.Results.There was no statistical difference between HT and IT, HT and ONT, or IT and ONT in SBP, DBP, fasting blood glucose, lipid panel, LH, FSH, and prolactin levels. The control group had lower SBP and BMI comparing with ONT, IT, and HT groups. There were no statistical differences found in DBP, fasting blood glucose, lipid panel, LH, FSH, or Prolactin.Conclusion.Metabolic profile in adolescent girls with PCOS is not affected by either the presence of hyperandrogenism or the degree of hyperandrogenism.
Neurocognitive Impairment in HIV-Infected Naïve Patients with Advanced Disease: The Role of Virus and Intrathecal Immune Activation
Authors: Airoldi Monica , Bandera Alessandra , Trabattoni Daria , Tagliabue Benedetta , Arosio Beatrice , Soria Alessandro , Rainone Veronica , Lapadula Giuseppe , Annoni Giorgio , Clerici Mario , Gori Andrea
Published: March 2012

Objective.To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naïve HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART).Methods.Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-γ, TNF-α, TGF-β1, and TGF-β2) and chemokines (MIP-1α, MIP-1β, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 <200/μL.Results.HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL-6 and MIP-1β, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1βremained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well.Conclusion.Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naïve HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation.
Visual Diagnosis: Pediatric Airway Emergency
Authors: Desai Bobby , Beattie Lars , Ryan Matthew F. , Falgiani Michael
Published: March 2012

We present a case of a potentially difficult airway emergency in a pediatric patient. After presentation, we briefly review critical differences between pediatric and adult airways and management of the airway during these emergencies.
Two‐Valued Control for a Second‐Order Plant with Additive External Disturbance
Authors: Rincon Alejandro , Londoño Felipe , Angulo Fabiola
Published: March 2012

In this work a two‐valued state feedback control for a plant of second order with known constant coefficients and an additive bounded disturbance is designed. In this controller the control signal can take only two possible values. The controller design is based on Lyapunov‐like function method, achieving the convergence of the tracking error to a user‐defined residual set. A boundedness condition for the user‐defined reference signal is defined, which is necessary to allow out‐put tracking. The developed scheme avoids large commutation rate of the control input. The controller design and stability analysis have important contributions with respect to closely related controllers based on the direct Lyapunov method, namely, (i) conditions to guarantee the expected convergence of the tracking error are established. These conditions are imposed on the reference signal and the extreme values of the control input. The stability analysis is developed by means of the Lyapunov‐like function method and the Barbalat′s Lemma and includes (ii) the bounded nature of the Lyapunov function, (iii) the monotonic convergence of the Lyapunov function to a residual set, and (iv) the asymptotic convergence of the tracking error to a residual set of user‐defined size.
New Analytic Solution to the Lane‐Emden Equation of Index 2
Authors: Motsa S. S. , Shateyi S.
Published: March 2012

We present two new analytic methods that are used for solving initial value problems that model polytropic and stellar structures in astrophysics and mathematical physics. The applicability, effectiveness, and reliability of the methods are assessed on the Lane‐Emden equation which is described by a second‐order nonlinear differential equation. The results obtained in this work are also compared with numerical results of Horedt (1986) which are widely used as a benchmark for testing new methods of solution. Good agreement is observed between the present results and the numerical results. Comparison is also made between the proposed new methods and existing analytical methods and it is found that the new methods are more efficient and have several advantages over some of the existing analytical methods.
Anomalous Hall Effect in Geometrically Frustrated Magnets
Authors: Boldrin D. , Wills A. S.
Published: March 2012

Geometrically frustrated conducting magnets display extraordinarily large anomalous Hall effects (AHEs) that could be used to realise materials required for the emerging field of spintronics. While the intrinsic Berry phase developed in collinear ferromagnets is well explained through the effects of spin-orbit interactions within the Karplus and Luttinger model, its origins in frustrated magnets are not. The direct space mechanism based on spin chirality that was originally applied to the pyrochlore Nd2Mo2O7appears unsatisfactory. Recently, an orbital description based on the Aharonov-Bohm effect has been proposed and applied to both the ferromagnetic pyrochlores Nd2Mo2O7and Pr2Ir2O7; the first of which features long-ranged magnetic order while the latter is a chiral spin liquid. Two further examples of geometrically frustrated conducting magnets are presented in this paper—the kagome-like Fe3Sn2and the triangular PdCrO2. These possess very different electronic structures to the 3-dimensional heavy-metal pyrochlores and provide new opportunities to explore the different origins of the AHE. This paper summarises the experimental findings in these materials in an attempt to unite the conflicting theoretical arguments.
TiO2-Based Photocatalytic Treatment of Raw and Constructed-Wetland Pretreated Textile Wastewater
Authors: Mahne Dunja , Lavrenčič Štangar Urška , Trebše Polonca , Griessler Bulc Tjaša
Published: March 2012

Approximately, 15% of the total textile colorant production is estimated to be lost during dyeing and processing of textile fibres. If left untreated, these wastewaters can represent a serious environmental threat. In the present paper a combination of photocatalytic and biological degradation of prepared textile wastewaters (simulation of real textile effluent) is presented. Samples have been monitored through the course of photocatalytic experiments: change in UV-VIS absorbance spectra and complete decolouration were achieved for all three tested dyed wastewaters; however, only partial COD removal was achieved with photocatalytic oxidation (PCOx) and photocatalytic ozonation (PCOz). Toxicity test (Vibrio fischeri) of untreated and pretreated (constructed wetland, CW) samples showed a decrease in toxicity values only for the red-dyed wastewater. Comparison of efficiency of PCOx and PCOz for decolouration and mineralization of three structurally different dyes (anthraquinone and two azo dyes) has been done. CW pretreatment caused faster decolouration and substantial COD removal in PCOx (up to 45%). Pretreatment also accelerated decolouration during PCOz, but it accelerated COD removal only in the case of red-dyed wastewater due to short irradiation times applied.
Periodic Solutions for Duffing Type p‐Laplacian Equation with Multiple Constant Delays
Authors: Zhang Hong , Meng Junxia
Published: March 2012

Using inequality techniques and coincidence degree theory, new results are provided concerning the existence and uniqueness of periodic solutions for the Duffing type p‐Laplacian equation with multiple constant delays of the form Moreover, an example is provided to illustrate the effectiveness of the results in this paper.
Surface Modification of Light Alloys by Low-Energy High-Current Pulsed Electron Beam
Authors: Zhang X. D. , Hao S. Z. , Grosdidier T. , Zou J. X. , Gao B. , Bolle B. , Allain-Bonasso N. , Qin Y. , Li X. N. , Dong C.
Published: March 2012

This paper reviews results obtained by the research groups developing the low-energy high-current pulsed electron beam (LEHCPEB) in Dalian (China) and Metz (France) on the surface treatment of light alloys. The pulsed electron irradiation induces an ultra-fast thermal cycle at the surface combined with the formation of thermal stress and shock waves. As illustrated for Mg alloys and Ti, this results in deep subsurface hardening (over several 100 μm) which improves the wear resistance. The analysis of the top surface melted surface of light alloys also often witnesses evaporation and condensation of chemical species. This phenomenon can significantly modify the melt chemistry and was also suggested to lead to the development of specific solidification textures in the rapidly solidified layer. The potential use of the LEHCPEB technique for producing thermomechanical treatments under the so-called heating mode and, thus, modify the surface crystallographic texture, and enhance solid-state diffusion is also demonstrated in the case of the FeAl intermetallic compound.