bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing embedded systems complexity with aspect-oriented model-driven engineering
Authors: Driver Cormac , Reilly Sean , Linehan Éamonn , Cahill Vinny , Clarke Siobhán
Published: January 2011

Model-driven engineering addresses issues of platform heterogeneity and code quality through the use of high-level system models and subsequent automatic transformations. Adoption of the model-driven software engineering paradigm for embedded systems necessitates specification of appropriate models of often complex systems. Modern embedded systems are typically composed of multiple functional and nonfunctional concerns, with the nonfunctional concerns (e.g., timing and performance) typically affecting the design and implementation of the functional concerns. The presence of crosscutting concerns makes specification of adequate platform-independent models a significant challenge. Aspect-oriented software development is a separation of concerns technique that decomposes systems into distinct features with minimal overlap. In this article, we illustrate how Theme/UML, an aspect-oriented modeling approach, can be used to separate embedded systems concerns and reduce complexity in design. We also present Model-Driven Theme/UML, a toolset for model-driven engineering of embedded systems that supports modularised design with Theme/UML and automatic transformations to composed models and source code.
Tightening the bounds on feasible preemptions
Authors: Ramaprasad Harini , Mueller Frank
Published: January 2011

Data caches are an increasingly important architectural feature in most modern computer systems. They help bridge the gap between processor speeds and memory access times. One inherent difficulty of using data caches in a real-time system is the unpredictability of memory accesses, which makes it difficult to calculate worst-case execution times (WCETs) of real-time tasks.

While cache analysis for single real-time tasks has been the focus of much research in the past, bounding the preemption delay in a multitask preemptive environment is a challenging problem, particularly for data caches.

This article makes multiple contributions in the context of independent, periodic tasks with deadlines less than or equal to their periods executing on a single processor.

1) For every task, we derive data cache reference patterns for all scalar and nonscalar references. These patterns are used to derive an upper bound on the WCET of real-time tasks.

2) We show that, when considering cache preemption effects, the critical instant does not occur upon simultaneous release of all tasks. We provide results for task sets with phase differences to prove our claim.

3) We develop a method to calculate tight upper bounds on the maximum number of possible preemptions for
each job
of a task and, considering the worst-case placement of these preemption points, derive a much tighter bound on its WCET. We provide results using both static-and dynamic-priority schemes.

Our results show significant improvements in the bounds derived. We achieve up to an order of magnitude improvement over two prior methods and up to half an order of magnitude over a third prior method for the
number of preemptions
, the
WCET
and the
response time
of a task. Consideration of the best-case and worst-case execution times of higher-priority jobs enables these improvements.
Scratchpad memory allocation for data aggregates via interval coloring in superperfect graphs
Authors: Li Lian , Xue Jingling , Knoop Jens
Published: January 2011

Existing methods place data or code in scratchpad memory (SPM) by relying on heuristics or resorting to integer programming or mapping it to a graph-coloring problem. In this article, the SPM allocation problem for arrays is formulated as an interval coloring problem. The key observation is that in many embedded C programs, two arrays can be modeled such that either their live ranges do not interfere or one contains the other (with good accuracy). As a result, array interference graphs often form a special class of superperfect graphs (known as comparability graphs), and their optimal interval colorings become efficiently solvable. This insight has led to the development of an SPM allocation algorithm that places arrays in an interference graph in SPM by examining its maximal cliques. If the SPM is no smaller than the clique number of an interference graph, then all arrays in the graph can be placed in SPM optimally. Otherwise, we rely on containment-motivated heuristics to split or spill array live ranges until the resulting graph is optimally colorable. We have implemented our algorithm in SUIF/machSUIF and evaluated it using a set of embedded C benchmarks from MediaBench and MiBench. Compared to a graph-coloring algorithm and an optimal ILP algorithm (when it runs to completion), our algorithm achieves close-to-optimal results and is superior to graph coloring for the benchmarks tested.
Mammalian Sperm Motility: Observation and Theory
Authors: Gaffney E.A. , Gadêlha H. , Smith D.J. , Blake J.R. , Kirkman-Brown J.C.
Published: January 2011

Mammalian spermatozoa motility is a subject of growing importance because of rising human infertility and the possibility of improving animal breeding. We highlight opportunities for fluid and continuum dynamics to provide novel insights concerning the mechanics of these specialized cells, especially during their remarkable journey to the egg. The biological structure of the motile sperm appendage, the flagellum, is described and placed in the context of the mechanics underlying the migration of mammalian sperm through the numerous environments of the female reproductive tract. This process demands certain specific changes to flagellar movement and motility for which further mechanical insight would be valuable, although this requires improved modeling capabilities, particularly to increase our understanding of sperm progression in vivo. We summarize current theoretical studies, highlighting the synergistic combination of imaging and theory in exploring sperm motility, and discuss the challenges for future observational and theoretical studies in understanding the underlying mechanics.
Fish Swimming and Bird/Insect Flight
Authors: Wu Theodore Yaotsu
Published: January 2011

This expository review is devoted to fish swimming and bird/insect flight. (a) The simple waving motion of an elongated flexible ribbon plate of constant width propagating a wave distally down the plate to swim forward in a fluid, initially at rest, is first considered to provide a fundamental concept on energy conservation. It is generalized to include variations in body width and thickness, with appended dorsal, ventral and caudal fins shedding vortices to closely simulate fish swimming, for which a nonlinear theory is presented for large-amplitude propulsion. (b) For bird flight, the pioneering studies on oscillatory rigid wings are discussed with delineating a fully nonlinear unsteady theory for a two-dimensional flexible wing with arbitrary variations in shape and trajectory to provide a comparative study with experiments. (c) For insect flight, recent advances are reviewed by items on aerodynamic theory and modeling, computational methods, and experiments, for forward and hovering flights with producing leading-edge vortex to yield unsteady high lift. (d) Prospects are explored on extracting prevailing intrinsic flow energy by fish and bird to enhance thrust for propulsion. (e) The mechanical and biological principles are drawn together for unified studies on the energetics in deriving metabolic power for animal locomotion, leading to the surprising discovery that the hydrodynamic viscous drag on swimming fish is largely associated with laminar boundary layers, thus drawing valid and sound evidences for a resounding resolution to the long-standing fish-swim paradox proclaimed by Gray (1936 , 1968 ).
Lagrangian Dynamics and Models of the Velocity Gradient Tensor in Turbulent Flows
Authors: Meneveau Charles
Published: January 2011

Many fundamental and intrinsic properties of small-scale motions in turbulence can be described using the velocity gradient tensor. This tensor encodes interesting geometric and statistical information such as the alignment of vorticity with respect to the strain-rate eigenvectors, rate of deformation and shapes of fluid material volumes, non-Gaussian statistics, and intermittency. In the inertial range of turbulence, similar properties can be described using the coarse-grained or filtered velocity gradient tensor. In this article we review various models that aim at understanding these phenomena using a small number of ordinary differential equations, written either as a low-dimensional dynamical system or as a set of stochastic differential equations. Typically these describe the Lagrangian evolution of the velocity gradient tensor elements following fluid particles and require models for the pressure Hessian and viscous effects. Sample results from various models are shown, and open challenges are highlighted.
Pulse Wave Propagation in the Arterial Tree
Authors: van de Vosse Frans N. , Stergiopulos Nikos
Published: January 2011

The beating heart creates blood pressure and flow pulsations that propagate as waves through the arterial tree that are reflected at transitions in arterial geometry and elasticity. Waves carry information about the matter in which they propagate. Therefore, modeling of arterial wave propagation extends our knowledge about the functioning of the cardiovascular system and provides a means to diagnose disorders and predict the outcome of medical interventions. In this review we focus on the physical and mathematical modeling of pulse wave propagation, based on general fluid dynamical principles. In addition we present potential applications in cardiovascular research and clinical practice. Models of short- and long-term adaptation of the arterial system and methods that deal with uncertainties in personalized model parameters and boundary conditions are briefly discussed, as they are believed to be major topics for further study and will boost the significance of arterial pulse wave modeling even more.
Rip Currents
Authors: Dalrymple Robert A. , MacMahan Jamie H. , Reniers Ad J.H.M. , Nelko Varjola
Published: January 2011

Rip currents are fast-moving flows, traveling “outward almost at right angles to the shore” ( Shepard 1936 ), creating a natural hazard for beachgoers, who suddenly find themselves in deep water. Field measurements and instrumentation, laboratory techniques, and numerical modeling have improved with time, enabling a more complete description of rip currents now. Surprisingly, there are many types of rip currents that can occur on beaches, and these currents are created by a wide variety of mechanisms that are presented here, along with numerical, physical, or field validation. We also show the potential for prediction schemes for use by lifeguards and beach managers.
Shear-Layer Instabilities: Particle Image Velocimetry Measurements and Implications for Acoustics
Authors: Morris Scott C.
Published: January 2011

The use of particle image velocimetry (PIV) to study the spatial and temporal features of unsteady fluid flow has increased dramatically in the past five to ten years. One particular application of PIV is to examine how shear-layer instabilities and turbulence lead to radiated sound. In this review, the basic operation of a PIV system is provided along with an introduction to the equations that relate unsteady fluid motion to sound. The references then illustrate how PIV is currently used in a number of canonical flow problems of interest in which the phenomena are dominated by shear-layer instabilities that lead to radiated noise. Specifically, cavity flows, flow over airfoils and cylinders, and finally jet flows are considered.
Aerodynamic Aspects of Wind Energy Conversion
Authors: Sørensen Jens Nørkær
Published: January 2011

This article reviews the most important aerodynamic research topics in the field of wind energy. Wind turbine aerodynamics concerns the modeling and prediction of aerodynamic forces, such as performance predictions of wind farms, and the design of specific parts of wind turbines, such as rotor-blade geometry. The basics of the blade-element momentum theory are presented along with guidelines for the construction of airfoil data. Various theories for aerodynamically optimum rotors are discussed, and recent results on classical models are presented. State-of-the-art advanced numerical simulation tools for wind turbine rotors and wakes are reviewed, including rotor predictions as well as models for simulating wind turbine wakes and flows in wind farms.
Short-term administration of rhGH increases markers of cellular proliferation but not milk protein gene expression in normal lactating women
Authors: Maningat Patricia D. , Sen Partha , Rijnkels Monique , Hadsell Darryl L. , Bray Molly S. , Haymond Morey W.
Published: January 2011

Growth hormone is one of few pharmacologic agents known to augment milk production in humans. We hypothesized that recombinant human GH (rhGH) increases the expression of cell proliferation and milk protein synthesis genes. Sequential milk and blood samples collected over four days were obtained from five normal lactating women. Following 24 h of baseline milk and blood sampling, rhGH (0.1 mg/kg/day) was administered subcutaneously once daily for 3 days. Gene expression changes were determined by microarray studies utilizing milk fat globule RNA isolated from each milk sample. Following rhGH administration, DNA synthesis and cell cycle genes were induced, while no significant changes were observed in the expression of milk synthesis genes. Expression of glycolysis and citric acid cycle genes were increased by day 4 compared with day 1, while lipid synthesis genes displayed a circadian-like pattern. Cell cycle gene upregulation occurred after a lag of ∼2 days, likely explaining the failure to increase milk production after only 3 days of rhGH treatment. We conclude that rhGH induces expression of cellular proliferation and metabolism genes but does not induce milk protein gene expression, as potential mechanisms for increasing milk production and could account for the known effect of rhGH to increase milk production following 7–10 days.
ZeGo: Development and Validation of a Short Questionnaire to Measure User Satisfaction with e-Government Portals
Authors: Bargas-Avila Javier A. , Orsini Sébastien , de Vito Marco , Opwis Klaus
Published: January 2011

In recent years, electronic services delivered via the World Wide Web have become increasingly important to governments. Substantial investments have been made to provide crucial services and information to citizens, businesses, and governmental institutions. This paper presents the development of a short questionnaire to measure user satisfaction with e-Governmental portals. After two validations of the instrument with federal e-Governmental portals in Switzerland, a final set of 15 items remained that were tested with 2498 participants. The final version showed high internal consistency (Cronbach's ) of .91, good item difficulties (.51 to .82), and discriminatory power coefficients (.49 to .81), as well as a moderate average homogeneity of .47. The survey was translated into five languages.
Montgomery Modular Multiplication on Reconfigurable Hardware: Systolic versus Multiplexed Implementation
Authors: Perin Guilherme , Gomes Mesquita Daniel , Martins João Baptista
Published: January 2011

This paper describes a comparison of two Montgomery modular multiplication architectures: a systolic and a multiplexed. Both implementations target FPGA devices. The modular multiplication is employed in modular exponentiation processes, which are the most important operations of some public-key cryptographic algorithms, including the most popular of them, the RSA. The proposed systolic architecture presents a high-radix implementation with a one-dimensional array of Processing Elements. The multiplexed implementation is a new alternative and is composed of multiplier blocks in parallel with the new simplified Processing Elements, and it provides a pipelined operation mode. We compare thetime×areaefficiency for both architectures as well as an RSA application. The systolic implementation can run the 1024 bits RSA decryption process in just 3.23 ms, and the multiplexed architecture executes the same operation in 4.36 ms, but the second approach saves up to 28% of logical resources. These results are competitive with the state-of-the-art performance.
γδT Cells Cross-Link Innate and Adaptive Immunity inMycobacterium tuberculosisInfection
Authors: Meraviglia Serena , El Daker Sary , Dieli Francesco , Martini Federico , Martino Angelo
Published: January 2011

Protective immunity against mycobacterial infections such asMycobacterium tuberculosisis mediated by interactions between specific T cells and activated antigen presenting cells. To date, many aspects of mycobacterial immunity have shown that innate cells could be the key elements that substantially may influence the subsequent adaptive host response. During the early phases of infection, innate lymphocyte subsets play a pivotal role in this context. Here we summarize the findings of recent investigations onγδT lymphocytes and their role in tuberculosis immunity.
Phase I Study of E7820, an Oral Inhibitor of Integrin α-2 Expression with Antiangiogenic Properties, in Patients with Advanced Malignancies
Authors: Mita Monica , Kelly Kevin R. , Mita Alain , Ricart Alejandro D. , Romero Ofelia , Tolcher Anthony , Hook Laurel , Okereke Chukwuemeka , Krivelevich Ilya , Rossignol Daniel P. , Giles Francis J. , Rowinsky Eric K. , Takimoto Chris
Published: January 2011

Purpose: This phase I study was conducted to characterize the safety profile, pharmacokinetics, pharmacodynamics, dose-limiting toxicity (DLT), and the maximum-tolerated dose of E7820, a novel oral sulfonamide derivative with antiangiogenic properties, when administered to patients with advanced solid malignancies.

Patients and Methods: Patients received single daily doses of E7820 orally for 28 days in cycle 1, followed by a 7-day no-treatment period, after which time-uninterrupted daily dosing ensued. The starting dose of E7820 was 10 mg/d, which was increased to 20, 40, 70, 100, and 200 mg/d in cohorts of new patients.

Results: Thirty-seven patients [21 male; median age 65 (40–82] were enrolled. At 100 mg/d, 1 patient experienced a DLT consisting of grade 3 neutropenia, thrombocytopenia, and elevated liver enzymes. At the 200-mg dose level, 2 patients experienced grade 4 thrombocytopenia and neutropenia. No partial or complete responses were observed; 8 patients had stable disease (≥4 months), including 5 patients with protracted stable disease exceeding 6 months. Mean time to maximum plasma concentration values ranged from 1 to 12 hours, whereas mean terminal half-life values ranged from 5.6 to 8.6 hours. Flow cytometric analysis of platelet integrin α-2 expression showed a sustained greater than 50% decrease beyond day 28 in 3 of 4 patients at 200 mg, whereas moderate (<30%) decreases were observed at 70- and 100-mg dose levels.

Conclusions: The recommended phase II dose of E7820 is 100 mg/d, based on a fasting schedule. E7820 downregulates integrin α-2 expression in surrogate tissues (platelets) and is associated with stable disease in a wide variety of heavily pretreated malignancies. Clin Cancer Res; 17(1); 193–200. ©2011 AACR.
Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor
Authors: Bourdeaut Franck , Lequin Delphine , Brugières Laurence , Reynaud Stéphanie , Dufour Christelle , Doz François , André Nicolas , Stephan Jean-Louis , Pérel Yves , Oberlin Odile , Orbach Daniel , Bergeron Christophe , Rialland Xavier , Fréneaux Paul , Ranchere Dominique , Figarella-Branger Dominique , Audry Georges , Puget Stéphanie , Evans D. Gareth , Pinas Joan Carles Ferreres , Capra Valeria , Mosseri Véronique , Coupier Isabelle , Gauthier-Villars Marion , Pierron Gaëlle , Delattre Olivier
Published: January 2011

Purpose: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT.

Experimental Design: hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification.

Results: Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P < 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy. Finally, the 2 years' overall survival was 7% in mutated and 29% in wild-type patients, mainly due to the worse outcome of RT in younger patients.

Conclusions: Our results show a high proportion of germline mutations in patients with RT that can be found at any age and up to 60% in the youngest patients. Genetic counseling is recommended given the low but actual risk of familial recurrence. Clin Cancer Res; 17(1); 31–8. ©2011 AACR.
Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition
Authors: Castelo-Branco Pedro , Zhang Cindy , Lipman Tatiana , Fujitani Mayumi , Hansford Loen , Clarke Ian , Harley Calvin B. , Tressler Robert , Malkin David , Walker Erin , Kaplan David R. , Dirks Peter , Tabori Uri
Published: January 2011

Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal.

Methods: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo.

Results: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo.

Conclusions: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin. Clin Cancer Res; 17(1); 111–21. ©2011 AACR.
EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells
Authors: Taddei Maria Letizia , Parri Matteo , Angelucci Adriano , Bianchini Francesca , Marconi Chiara , Giannoni Elisa , Raugei Giovanni , Bologna Mauro , Calorini Lido , Chiarugi Paola
Published: January 2011

EphA2 kinase regulates cell shape, adhesion, and motility and is frequently overexpressed in several cancers, including melanoma, prostate, breast, and colon cancers and lung carcinoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 in tumor progression is still debated. In melanoma, EphA2 has been reported to affect cell migration and invasiveness allowing cells to move by a proteolysis-independent strategy, commonly referred as amoeboid motility. With the aim to understand the role of EphA2 in prostate cancer metastatic spreading, we stably silenced EphA2 expression in a model of aggressive metastatic prostate carcinoma. Our results show that EphA2 drives the metastatic program of prostate carcinoma, although its involvement greatly differs among metastatic steps. Indeed, EphA2 expression (i) greatly affects prostate carcinoma cell motility style, guiding an amoeboid movement based on Rho-mediated cell rounding and independent from metalloprotases, (ii) is ineffective on transendothelial migration, adhesion onto extracellular matrix proteins, and on resistance to anoikis, (iii) regulates clonogenic potential of prostate carcinoma, thereby increasing anchorage-independent growth and self-renewal, prostasphere formation, tumor onset, dissemination to bone, and growth of metastatic colonies. Our finding indicate that EphA2-overexpressing prostate carcinoma cells gain an invasive benefit from their amoeboid motility style to escape from primary tumors and then, enhancing their clonogenic potential successfully target bone and grow metastases, thereby acknowledging EphA2 as a target for antimetastatic therapy of aggressive prostate cancers. Mol Cancer Res; 9(2); 149–60. ©2011 AACR.
The Homologous Recombination Protein RAD51D Mediates the Processing of 6-Thioguanine Lesions Downstream of Mismatch Repair
Authors: Rajesh Preeti , Litvinchuk Alexandra V. , Pittman Douglas L. , Wyatt Michael D.
Published: January 2011

Thiopurines are extensively used as immunosuppressants and in the treatment of childhood cancers, even though there is concern about therapy-induced leukemias and myelodysplastic syndromes resulting from thiopurine use. Following metabolic activation, thiopurines are incorporated into DNA and invoke mismatch repair (MMR). Recognition of 6-thioguanine (6-thioG) in DNA by key MMR proteins results in cell death rather than repair. There are suggestions that homologous recombination (HR) is involved downstream of MMR following thiopurine treatment, but the precise role of HR is poorly understood. In this study, we demonstrate that cells deficient in RAD51D (a RAD51 paralogue) are extremely sensitive to 6-thioG. This sensitivity is almost completely rescued by the deletion of Mlh1, which suggests that HR is involved in the repair of the 6-thioG–induced recombinogenic lesions generated by MMR. Furthermore, 6-thioG induces chromosome aberrations in the Rad51d-deficient cells. Interestingly, Rad51d-deficient cells show a striking increase in the frequency of triradial and quadriradial chromosomes in response to 6-thioG therapy. The presence of these chromatid exchange–type aberrations indicates that the deficiency in RAD51D-dependent HR results in profound chromosomal damage precipitated by the processing of 6-thioG by MMR. The radials are notable as an important source of chromosomal translocations, which are the most common class of mutations found in hematologic malignancies. This study thus suggests that HR insufficiency could be a potential risk factor for the development of secondary cancers that result from long-term use of thiopurines in patients. Mol Cancer Res; 9(2); 206–14. ©2011 AACR.
Protective Role of Heat Shock Proteins in Parkinson’s Disease
Authors: Aridon Paolo , Geraci Fabiana , Turturici Giuseppina , D’Amelio Marco , Savettieri Giovanni , Sconzo Gabriella
Published: January 2011

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. Despite a large amount of research, the pathogenetic mechanism of these diseases has not yet been clarified. Abnormal protein folding, oxidative stress, mitochondrial dysfunction, and apoptotic mechanisms have all been reported as causes of neurodegenerative diseases in association with neuroinflammatory mechanisms which, by generating deleterious molecules, could promote the cascade of events leading to neurodegeneration. Heat shock proteins (HSPs) play a central role in preventing protein misfolding and inhibiting apoptotic activity, and represent a class of proteins potentially involved in PD pathogenesis. The present review will focus on two HSPs, HSP70 and HSP90, with the aim of specifying their role in PD pathogenesis.
Glutathione S-Transferase M1, GSTT1 and GSTP1 Genetic Polymorphisms and the Risk of Age-Related Macular Degeneration
Authors: Güven Mehmet , Görgün Ebru , Ünal Mustafa , Yenerel Melda , Batar Bahadır , Küçümen Beril , Dinç Umut Aslı , Güven Gülgün S. , Ulus Tümer , Yüksel Adnan
Published: January 2011

Purpose: To determine the possible effects of glutathione S-transferase (GST) M1, GSTT1 and GSTP1 genetic polymorphisms on the risk of developing age-related macular degeneration (AMD). Patients and Methods: This case-control study included a total of 120 patients with AMD (65 with dry-type AMD and 55 with wet-type AMD) and 198 disease-free controls. GSTM1 and GSTT1 polymorphisms were analyzed by using a multiplex polymerase chain reaction (PCR), and GSTP1 polymorphism was detected by real-time PCR assay. Results:GSTM1-null genotype was significantly associated with the development of AMD (p = 0.01, OR = 1.82, 95% CI = 1.14–2.91). Stratification by AMD subtypes revealed a significant relationship between GSTM1-null genotype and dry-type AMD (p = 0.02, OR = 1.98, 95% CI = 1.10–3.53). In a stepwise regression model, only GSTM1-null genotype was significantly associated with the development of AMD (p = 0.01, OR = 1.77, 95% CI = 1.11–2.81). Conclusions: Our findings suggest that genetic polymorphisms of GST may have a role in the development of AMD.
Impaired Ideomotor Limb Apraxia in Cortical and Subcortical Dementia: A Comparison of Alzheimer’s and Huntington’s Disease
Authors: Holl Anna K. , Ille Rottraut , Wilkinson Leonora , Otti Daniela V. , Hödl Elfriede , Herranhof Brigitte , Reisinger Karin M. , Müller Nicole , Painold Annamaria , Holl Etienne M. , Letmaier Martin , Bonelli Raphael M.
Published: January 2011

Background: Although ideomotor limb apraxia is often considered to occur only in dementia with cortical involvement like Alzheimer’s disease (AD), it is also frequently seen in dementia with subcortical degeneration like Huntington’s disease (HD). Methods: To assess the occurrence of ideomotor limb apraxia, 46 patients with HD (27 men) and 37 patients with AD (16 men), matched for cognitive performance, were assessed with an apraxia test battery containing tests of the imitation of meaningless hand and finger gestures, the performance of meaningful gestures and of pantomimic movements. Results: There was a high frequency of ideomotor limb apraxia in both AD and HD patients. For the assessment of hands’ imitation 13.5% of the AD patients and 41.3% of the HD patients were apraxic, for fingers’ imitation 21.6% (AD) and 41.3% (HD) were apraxic, for gestures 27.0% (AD) and 32.6% (HD), and for the assessment of pantomimic movements 24.3% (AD) and 52.2% (HD) showed apraxia. In the AD patients, disease severity was related to the occurrence of apraxia. Conclusions: Ideomotor limb apraxia is a common sign in both groups of patients, occurring in a high percentage. For particular neuropsychological deficits, including ideomotor limb apraxia, a division of dementia in a subcortical and cortical subtype seems to be clinically not meaningful.
Evaluation of Symptomatic Carotid Plaques by Tissue Characterization Using Integrated Backscatter Ultrasound and Magnetic Resonance Imaging
Authors: Yamada Kiyofumi , Kawasaki Masanori , Yoshimura Shinichi , Enomoto Yukiko , Asano Takahiko , Minatoguchi Shinya , Iwama Toru
Published: January 2011

Background: Unstable carotid plaques that consist of large lipid pool and intraplaque hemorrhage are more likely to cause cerebral infarction. We previously developed an integrated backscatter (IBS) ultrasound color-coded mapping method to evaluate the tissue characteristics of plaques. The purpose of this study was to determine whether 3-dimensional IBS color-coded mapping and signal intensity ratio (SIR) from magnetic resonance imaging (MRI) could distinguish the early symptomatic plaques from late symptomatic plaques. Methods: We performed quantitative tissue characterization of carotid plaques measuring IBS values and the SIR from T1-weighted MRI images in 95 carotid plaques (>50% stenosis) in 95 patients (45 symptomatic, 50 asymptomatic). Results: The percent unstable component volume (UCV) that consisted of lipid pool and intraplaque hemorrhage and the SIR of symptomatic carotid plaques were higher than those of asymptomatic plaques (57.8 ± 25.1 vs. 46.8 ± 25.1%, p = 0.036; 1.31 ± 0.25 vs. 1.21 ± 0.26, p = 0.047). In patients that were imaged within 3 days of symptom onset, the %UCV and SIR were significantly higher than the values in patients that were imaged 30–180 days after symptom onset (73.1 ± 18.4 vs. 38.7 ± 18.4%, p < 0.001; 1.38 ± 0.22 vs. 1.22 ± 0.26, p = 0.031). From the analysis of receiver operating characteristic curves, a %UCV of 50% (measured by IBS) and an SIR of 1.25 (measured by MRI) were the most optimal cutoff values for identifying early symptomatic plaques. Conclusions: Noninvasive quantitative tissue characterization of atherosclerotic lesions in carotid arteries using IBS ultrasound and MRI is useful to distinguish early symptomatic plaques from late symptomatic plaques.
Mortality Benefit in PLATO Cannot Be Explained by Antiplatelet Properties of Ticagrelor
Authors: Serebruany Victor L.
Published: January 2011

The striking success of ticagrelor in PLATO when compared with recent important but far less impressive antiplatelet trials suggests the fundamental difference of ticagrelor from thienopyridines, such as ticlopidone, clopidogrel, and prasugrel. In fact, being a P2Y12 platelet receptor inhibitor, ticagrelor does not belong to the thienopyridines. The agent is a carbocyclic nucleoside, representing a ‘first-in-class’ cyclopentyl-triazolo-pyrimidine. The chemical structure of ticagrelor indicates that its primary mechanism of action may be via up-regulating plasma and intracellular adenosine content, especially considering the obvious similarity of their molecules. Since ticagrelor does not require hepatic metabolization, an adenosine-promoting mechanism of action is the most likely responsible pathway. Some of the delayed and growing mortality advantage of ticagrelor over clopidogrel cannot be explained by pure antiplatelet properties of the drug, but may be attributed to the off-target pleiothropic effects of the novel agent. An adenosine-mediated mechanism is most likely responsible for the fundamental difference of ticagrelor from established antiplatelet agents, and resulted in less heart failure deaths, and reduction of fatal arrhythmias. However, massive prevention of vascular death mismatched with conventional myocardial infarction rates, and reduction of sepsis-related mortality still lacks reasonable explanation, being under the scope of the regulatory agencies around the world. Future randomized trials of ticagrelor in acute heart failure, sudden death prevention, and treatment of atrial fibrillation are warranted, and may expand our understanding of the mechanism of action of pyrimidines in general, and ticagrelor in particular.
Assessment of Lower Limb Microcirculation: Exploring the Reproducibility and Clinical Application of Laser Doppler Techniques
Authors: Klonizakis M. , Manning G. , Donnelly R.
Published: January 2011

Purpose of Study: Non-invasive laser Doppler fluximetry (LDF) and laser Doppler imaging (LDI), combined with iontophoresis, have been used to study the microcirculation in a range of clinical conditions including lower limb venous disease. A prerequisite for an accurate measurement tool is that it is reproducible. However, there is currently no literature with respect to the reproducibility of LDF and LDI combined with iontophoresis in the lower limb (in general) and in the upright position (in specific). Furthermore, the two techniques have been used interchangeably by researchers and the association between these two different measurement methods has not been explored, nor have the factors that affect them been well described. Thus the aim of this study was to determine the reproducibility of LDF and LDI with iontophoresis in the lower limb and investigate factors that influence their clinical application. Procedures: Cutaneous microvascular responses in the lower limb were measured in the supine and standing positions using LDF and LDI combined with iontophoretic administration of endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside) vasodilators in 25 patients with uncomplicated isolated superficial venous incompetence (ISVI) and 26 healthy controls. Results: Maximum perfusion had the best reproducibility assessed by LDF (CV 20.5–24.3%) and LDI (15.8–17.6%). Both techniques were positively influenced by iontophoretic dose (e.g. p = 0.0001 for LDF) and the use of vasodilator agents (e.g. p = 0.0001 for LDF), but negatively influenced in the standing position and/or in the presence of ISVI (p = 0.0016 and 0.045, respectively, for LDF). There was a statistically significant positive relationship between the two techniques, for example ACh maximum perfusion versus LDF ACh maximum perfusion (r = 0.404, p = 0.016). Conclusions: Both techniques are reproducible, in line with similar studies undertaken in other areas of the human body, and provide useful information for the study of the lower-limb microcirculation. Direct comparison between techniques based on absolute numbers should be avoided and the technique choice should be based on individual study needs.
Prevention of Follicular Penetration: Barrier-Enhancing Formulations against the Penetration of Pollen Allergens into Hair Follicles
Authors: Meinke M.C. , Patzelt A. , Richter H. , Schanzer S. , Sterry W. , Filbry A. , Bohnsack K. , Rippke F. , Galecka J. , Fölster-Holst R. , Lademann J.
Published: January 2011

The hair follicles could be a reservoir for topically applied substances. They are not only surrounded by a close network of blood capillaries, which makes them interesting for drug delivery, but they are also the host of dendritic cells, which are important for immunomodulation. Previously, pollen allergens were shown to penetrate into the hair follicles. The application of barrier-enhancing formulations might represent an effective strategy to prevent pollen protein penetration into the hair follicle. In the present study, porcine skin areas were pretreated with 4 barrier-enhancing emulsions. One skin area served as control and remained without pretreatment. Afterwards, fluorescein-isothiocyanate-labeled grass pollen proteins were applied to the porcine skin samples, and their penetration was investigated via fluorescent laser scanning microscopy. It was shown that the barrier-enhancing formulations were able to significantly reduce the penetration of exogenous proteins into the hair follicles, the extent of such reduction depending on the formulation.
Intraarterial Administration of Bone Marrow Mononuclear Cells in Patients With Critical Limb Ischemia
Authors: Walter Dirk H. , Krankenberg Hans , Balzer Jörn O. , Kalka Christoph , Baumgartner Iris , Schlüter Michael , Tonn Torsten , Seeger Florian , Dimmeler Stefanie , Lindhoff-Last Edelgard , Zeiher Andreas M. ,   for the PROVASA Investigators
Published: January 2011

Background—

Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality. There is no effective pharmacological therapy available. Injection of autologous bone marrow-derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking.

Methods and Results—

Forty patients with critical limb ischemia were included in a multicenter, phase II, double-blind, randomized-start trial to receive either intraarterial administration of BM-MNC or placebo followed by active treatment with BM-MNC (open label) after 3 months. Intraarterial administration of BM-MNC did not significantly increase ankle-brachial index and, thus, the trial missed its primary end point. However, cell therapy was associated with significantly improved ulcer healing (ulcer area, 3.2±4.7 cm
2
to 1.89±3.5 cm
2
[
P
=0.014] versus placebo, 2.92±3.5 cm
2
to 2.89±4.1 cm
2
[
P
=0.5]) and reduced rest pain (5.2±1.8 to 2.2±1.3 [
P
=0.009] versus placebo, 4.5±2.4 to 3.9±2.6 [
P
=0.3]) within 3 months. Limb salvage and amputation-free survival rates did not differ between the groups.

Repeated BM-MNC administration and higher BM-MNC numbers and functionality were the only independent predictors of improved ulcer healing. Ulcer healing induced by repeated BM-MNC administration significantly correlated with limb salvage (
r
=0.8;
P
<0.001).

Conclusions—

Intraarterial administration of BM-MNC is safe and feasible and accelerates wound healing in patients without extensive gangrene and impending amputation. These exploratory findings of this pilot trial need to be confirmed in a larger randomized trial in patients with critical limb ischemia and stable ulcers.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00282646.
Simple or Complex Stenting for Bifurcation Coronary Lesions
Authors: Behan Miles W. , Holm Niels R. , Curzen Nicholas P. , Erglis Andrejs , Stables Rodney H. , de Belder Adam J. , Niemelä Matti , Cooter Nina , Chew Derek P. , Steigen Terje K. , Oldroyd Keith G. , Jensen Jan S. , Lassen Jens Flensted , Thuesen Leif , Hildick-Smith David
Published: January 2011

Background—

Controversy persists regarding the correct strategy for bifurcation lesions. Therefore, we combined the patient-level data from 2 large trials with similar methodology: the NORDIC Bifurcation Study (NORDIC I) and the British Bifurcation Coronary Study (BBC ONE).

Methods and Results—

Both randomized trials compared simple (provisional T-stenting) versus complex techniques, using drug-eluting stents. In the simple group (n=457), 129 patients had final kissing balloon dilatation in addition to main vessel stenting, and 16 had T-stenting. In the complex group (n=456), 272 underwent crush, 118 culotte, and 59 T-stenting techniques. A composite end point at 9 months of all-cause death, myocardial infarction, and target vessel revascularization occurred in 10.1% of the simple versus 17.3% of the complex group (hazard ratio 1.84 [95% confidence interval 1.28 to 2.66],
P
=0.001). Procedure duration, contrast, and x-ray dose favored the simple approach. Subgroup analysis revealed similar composite end point results for true bifurcations (n=657, simple 9.2% versus complex 17.3%; hazard ratio 1.90 [95% confidence interval 1.22 to 2.94],
P
=0.004), wide-angled bifurcations >60 to 70° (n=217, simple 9.6% versus complex 15.7%; hazard ratio 1.67 [ 95% confidence interval 0.78 to 3.62],
P
=0.186), large (≥2.75 mm) diameter side branches (n=281, simple 10.4% versus complex 20.7%; hazard ratio 2.42 [ 95% confidence interval 1.22 to 4.80],
P
=0.011), longer length (>5 mm) ostial side branch lesions (n=464, simple 12.1% versus complex 19.1%; hazard ratio 1.71 [95% confidence interval 1.05 to 2.77],
P
=0.029), or equivalent sized vessels (side branch <0.25 mm smaller than main vessel) (n=108, simple 12.0% versus complex 15.5%; hazard ratio 1.35 [95% confidence interval 0.48 to 3.70],
P
=0.57).

Conclusions—

For bifurcation lesions, a provisional single-stent approach is superior to systematic dual stenting techniques in terms of safety and efficacy. A complex approach does not appear to be beneficial in more anatomically complicated lesions.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT 00376571 and NCT 00351260.
Impact of Drug-Eluting Stents and Diabetes Mellitus in Patients With Coronary Bifurcation Lesions: A Survey From the Italian Society of Invasive Cardiology
Authors: Capodanno Davide , Tamburino Corrado , Sangiorgi Giuseppe M. , Romagnoli Enrico , Colombo Antonio , Burzotta Francesco , Gasparini Gabriele L. , Bolognese Leonardo , Paloscia Leonardo , Rubino Paolo , Sardella Gennaro , Briguori Carlo , Ettori Federica , Franco Gianfranco , Di Girolamo Domenico , Sheiban Imad , Piatti Luigi , Greco Cesare , Petronio Anna Sonia , Loi Bruno , Lyoi Ernesto , Benassi Alberto , Patti Aldo , Gaspardone Achille , De Servi Stefano ,   for the I-BIGIS Study Group
Published: January 2011

Background—

We investigated the long-term impact of different stent types and diabetes mellitus (DM) in patients undergoing percutaneous coronary intervention (PCI) of bifurcation lesions, based on a large multicenter survey endorsed by the Italian Society of Invasive Cardiology.

Methods and Results—

Relative benefits of drug eluting stent (DES) over bare metal stent (BMS) in patients with (n=1049) and without (n=3020) DM were analyzed with extensive multivariable adjustment. At 3 years, stenting with DES was associated with lower adjusted risk of major adverse cardiac events (MACE, adjusted hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.15 to 0.49,
P
<0.001), cardiac death, and target lesion revascularization in DM patients but failed to demonstrate any significant benefit in patients without DM.

Conclusions—

In a large observational registry with admitted potential for selection bias and residual confounding, DES in DM patients with coronary bifurcation lesions were associated with improved outcomes in terms of MACE, cardiac death, and repeat revascularization at long-term follow up. These figures were not replicated in non-DM subjects.
Melody Valve Implantation Into the Branch Pulmonary Arteries for Treatment of Pulmonary Insufficiency in an Ovine Model of Right Ventricular Outflow Tract Dysfunction Following Tetralogy of Fallot Repair
Authors: Robb J. Daniel , Harris Matthew A. , Minakawa Masahito , Rodriguez Evelio , Koomalsingh Kevin J. , Shuto Takashi , Shin David C. , Dori Yoav , Glatz Andrew C. , Rome Jonathan J. , Gorman Robert C. , Gorman Joseph H. , Gillespie Matthew J.
Published: January 2011

Background—

Transannular patch (TAP) repair of tetralogy of Fallot often results in significant right ventricular outflow tract (RVOT) dilation and distortion. We hypothesized that insertion of Melody valves into the proximal right and left branch pulmonary arteries (PAs) would reduce pulmonary regurgitation fraction (PRF) in an ovine model of pulmonary insufficiency and dilated RVOT.

Methods and Results—

Ten sheep underwent baseline cardiac catheterization, surgical pulmonary valvectomy, and TAP placement. A subset (n=5) had Melody valves (2 devices per animal) inserted into the proximal right and left PAs during the surgical procedure. Melody valves were placed distal to the right-upper-lobe (RUL) artery branch, leaving the RUL “unprotected.” Preoperative MRIs (n=5) were used to determine baseline RV ejection fraction (RVEF) and left ventricular (LV) EF. All surviving animals (n=9) underwent MRI and catheterization 6 weeks postsurgery.

Mean PRF was lower in the Melody valve group (15±6% versus 37±3%;
P
=0.014). The unprotected RUL was responsible for 64% of the PRF measured in the Melody valve group. In the non-Melody group, the RVEF was lower than baseline (
P
=0.003) and than in the Melody group (
P
=0.05). The LVEF was also lower in the non-Melody group versus baseline (
P
=0.004) and versus Melody (
P
=0.01).

Conclusions—

Bilateral branch PA Melody valve implantation significantly reduced PRF and altered RV and LV function favorably in a model of TAP for tetralogy of Fallot. This novel intervention may offer potential benefit in treating patients with anatomically heterogeneous disease of the RVOT.