bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH PLANNING FOR RACING GAMES
Authors: TAN CHARLIE IRAWAN , CHEN CHANG-MIN , TAI WEN-KAI , CHANG CHIN-CHEN
Published: October 2010

We propose a set of path planning tools including path generator, cost map generator, and path editor for racing games. The user can define the race by providing a racetrack as a 3D model and weights of the devised turn and heuristic functions in our system. Then, the proposed cost map generator automatically generates necessary information of the racetrack including cost map and distance to finish of any position on the race track. Different from the traditional A* problem, in our research the obstacles are dynamic and there are multiple sources and destinations. Our approach generates the path of each racer on the basis of time slots to which the path finding method applies on the fly. To further guarantee the quality of the path, we implement path smoothing using a Gaussian filter and provide an off-line path editor that allows users to edit the path in time-space domain intuitively, flexibly, and effectively. Our tools have been verified in a horse racing game to generate natural racer behaviors, demonstrating realistic and exciting racing.
ERGODIC PROPERTIES OF BOGOLIUBOV AUTOMORPHISMS IN FREE PROBABILITY
Authors: FIDALEO FRANCESCO , MUKHAMEDOV FARRUKH
Published: October 2010

We show that some C*-dynamical systems obtained by free Fock quantization of classical ones, enjoy ergodic properties much stronger than their boson or fermion analogous. Namely, if the classical dynamical system (X, T, μ) is ergodic but not weakly mixing, then the resulting free quantized system (𝔊, α) is uniquely ergodic (w.r.t. the fixed point algebra) but not uniquely weak mixing. The same happens if we quantize a classical system (X, T, μ) which is weakly mixing but not mixing. In this case, the free quantized system is uniquely weak mixing but not uniquely mixing. Finally, a free quantized system arising from a classical mixing dynamical system, will be uniquely mixing. In such a way, it is possible to exhibit uniquely weak mixing and uniquely mixing C*-dynamical systems whose Gelfand–Naimark–Segal representation associated to the unique invariant state generates a von Neumann factor of one of the following types: I∞, II1, IIIλwhere λ ∈ (0, 1]. The resulting scenario is then quite different from the classical one. In fact, if a classical system is uniquely mixing, it is conjugate to the trivial one consisting of a singleton. For the sake of completeness, the results listed above are extended to the q-Commutation Relations, provided [Formula: see text]. The last result has a self-contained meaning as we prove that the involved C*-dynamical systems based on the q-Commutation Relations are conjugate to the corresponding one arising from the free case (i.e. q = 0), at least if [Formula: see text].
AXIOMATIC CHARACTERIZATION OF THE MEAN FUNCTION ON TREES
Authors: McMORRIS F. R. , MULDER HENRY MARTYN , ORTEGA OSCAR
Published: October 2010

A mean of a sequence π = (x1, x2, …, xk) of elements of a finite metric space (X, d) is an element x for which [Formula: see text] is minimum. The function Mean whose domain is the set of all finite sequences on X and is defined by Mean (π) = {x|x is a mean of π} is called the mean function on X. In this note, the mean function on finite trees is characterized axiomatically.
SUB-COLORING AND HYPO-COLORING INTERVAL GRAPHS
Authors: GANDHI RAJIV , GREENING BRADFORD , PEMMARAJU SRIRAM , RAMAN RAJIV
Published: October 2010

In this paper, we study the sub-coloring and hypo-coloring problems on interval graphs. These problems have applications in job scheduling and distributed computing and can be used as "subroutines" for other combinatorial optimization problems. In the sub-coloring problem, given a graph G, we want to partition the vertices of G into minimum number of sub-color classes, where each sub-color class induces a union of disjoint cliques in G. In the hypo-coloring problem, given a graph G, and integral weights on vertices, we want to find a partition of the vertices of G into sub-color classes such that the sum of the weights of the heaviest cliques in each sub-color class is minimized. We present a "forbidden subgraph" characterization of graphs with sub-chromatic number k and use this to derive a 3-approximation algorithm for sub-coloring interval graphs. For the hypo-coloring problem on interval graphs, we first show that it is NP-complete, and then via reduction to the max-coloring problem, show how to obtain an O( log n)-approximation algorithm for it.
CONVEX DRAWINGS OF INTERNALLY TRICONNECTED PLANE GRAPHS ON O(n2) GRIDS
Authors: ZHOU XIAO , NISHIZEKI TAKAO
Published: October 2010

In a convex grid drawing of a plane graph, every edge is drawn as a straight-line segment without any edge-intersection, every vertex is located at a grid point, and every facial cycle is drawn as a convex polygon. A plane graph G has a convex drawing if and only if G is internally triconnected. It has been known that an internally triconnected plane graph G of n vertices has a convex grid drawing on a grid of O(n3) area if the triconnected component decomposition tree of G has at most four leaves. In this paper, we improve the area bound O(n3) to O(n2), which is optimal up to a constant factor. More precisely, we show that G has a convex grid drawing on a 2n × 4n grid. We also present an algorithm to find such a drawing in linear time.
PARTIAL RESULT ON HADWIGER'S CONJECTURE
Authors: SONG ZI-XIA
Published: October 2010

Let D = (d1, d2, …, dn) be a graphic sequence with 0 ≤ d1≤ d2≤ ⋯ ≤ dn. Any simple graph G with D its degree sequence is called a realization of D. Let R[D] denote the set of all realizations of D. We say that D is H-free if no graph in R[D] contains H as an induced subgraph. In this paper, we prove that Hadwiger's Conjecture is true for graphs whose degree sequences are claw-free or [Formula: see text]-free.
HAJÓS-LIKE THEOREM FOR GROUP COLORING
Authors: AN XINHUI , WU BAOYINDURENG
Published: October 2010

The group coloring of graphs is a new kind of graph coloring, introduced by Jaeger et al. in 1992, and the group chromatic number of a graph G is denoted by χg (G). In this note, we prove that for a positive integer k, a graph G with χg (G)>k can be obtained from any complete bipartite graph G0 with χg(G0)>k by certain types of graph operations.
Power gating
Authors: Shin Youngsoo , Seomun Jun , Choi Kyu-Myung , Sakurai Takayasu
Published: October 2010

Power Gating has become one of the most widely used circuit design techniques for reducing leakage current. Its concept is very simple, but its application to standard-cell VLSI designs involves many careful considerations. The great complexity of designing a power-gated circuit originates from the side effects of inserting current switches, which have to be resolved by a combination of extra circuitry and customized tools and methodologies. In this tutorial we survey these design considerations and look at the best practice within industry and academia. Topics include output isolation and data retention, current switch design and sizing, and physical design issues such as power networks, increases in area and wirelength, and power grid analysis. Designers can benefit from this tutorial by obtaining a better understanding of implications of power gating during an early stage of VLSI designs. We also review the ways in which power gating has been improved. These include reducing the sizes of switches, cutting transition delays, applying power gating to smaller blocks of circuitry, and reducing the energy dissipated in mode transitions. Power Gating has also been combined with other circuit techniques, and these hybrids are also reviewed. Important open problems are identified as a stimulus to research.
An in-place search algorithm for the resource constrained scheduling problem during high-level synthesis
Authors: Yu Cheng-Juei , Wu Yi-Hsin , Wang Sheng-De
Published: October 2010

We propose an in-place search algorithm for computing the exact solutions to the resource constrained scheduling problem. This algorithm supports operation chaining, pipelining and multicycling in the underlying scheduling problem. Based on two lower-bound estimation mechanisms that are capable of predicting the criterion values of search nodes represented by partially scheduled data flow graphs, the proposed algorithm can effectively prune the nonpromising search space and finds the optimum usually several times faster than existing techniques. As opposed to existing search-based scheduling techniques whose space complexity is squared or exponential in the search depth, our approach requires only a constant storage space during the traversal of the search tree. The low space complexity is accomplished by using a combination-generating algorithm, which leads our approach to visit search nodes in such a way that each one is obtained by making only a small change to its sibling without keeping any parent nodes in memory. Experimental results on several well known benchmarks with varying resource constraints show the effectiveness of the proposed algorithm.
Partitioning techniques for partially protected caches in resource-constrained embedded systems
Authors: Lee Kyoungwoo , Shrivastava Aviral , Dutt Nikil , Venkatasubramanian Nalini
Published: October 2010

Increasing exponentially with technology scaling, the soft error rate even in earth-bound embedded systems manufactured in deep subnanometer technology is projected to become a serious design consideration. Partially protected cache (PPC) is a promising microarchitectural feature to mitigate failures due to soft errors in power, performance, and cost sensitive embedded processors. A processor with PPC maintains two caches, one protected and the other unprotected, both at the same level of memory hierarchy. The intuition behind PPCs is that not all data in the application is equally prone to soft errors. By finding and mapping the data that is more prone to soft errors to the protected cache, and error-resilient data to the unprotected cache, failures induced by soft errors can be significantly reduced at a minimal power and performance penalty. Consequently, the effectiveness of PPCs critically hinges on the compiler's ability to partition application data into error-prone and error-resilient data. The effectiveness of PPCs has previously been demonstrated on multimedia applications—where an obvious partitioning of data exists, the multimedia data is inherently resilient to soft errors, and the rest of the data and the entire code is assumed to be error-prone. Since the amount of multimedia data is a quite significant component of the entire application data, this obvious partitioning is quite effective. However, no such obvious data and code partitioning exists for general applications. This severely restricts the applicability of PPCs to data caches and instruction caches in general. This article investigates vulnerability-based partitioning schemes that are applicable to applications in general and effectively reduce failures due to soft errors at minimal power and performance overheads.

Our experimental results on an HP iPAQ-like processor enhanced with PPC architecture, running benchmarks from the MiBench suite demonstrate that our partitioning heuristic efficiently finds page partitions for data PPCs that can reduce the failure rate by 48% at only 2% performance and 7% energy overhead, and finds page partitions for instruction PPCs that reduce the failure rate by 50% at only 2% performance and 8% energy overhead, on average.
On the completeness of the polymorphic gate set
Authors: Li Zhifang , Luo Wenjian , Yue Lihua , Wang Xufa
Published: October 2010

Polymorphic gates are special kinds of logic gates that can exhibit different functions under the control of environmental parameters, such as light, temperature, and VDD. These polymorphic gates can be used to build polymorphic circuits that perform different functions under different environments. Because polymorphic gates are different from traditional logic gates, the existent completeness theory for the traditional logic gate set is not suitable for the polymorphic gate set. So far, only the definition of the complete polymorphic gate set is given. There is no approach to judging whether a given polymorphic gate set is complete. The contributions of this article include three aspects. First, the impact of logic-1 and logic-0 on the completeness of the polymorphic gate set is discussed. Second, the theory and two related algorithms for judging the completeness of polymorphic gate sets with two modes are given. Finally, the theory and related algorithms for complete polymorphic gate sets with more than two modes are proposed.
Complexity of 3-D floorplans by analysis of graph cuboidal dual hardness
Authors: Wang Renshen , Young Evangeline , Cheng Chung-Kuan
Published: October 2010

Interconnect dominated electronic design stimulates a demand for developing circuits on the third dimension, leading to 3-D integration. Recent advances in chip fabrication technology enable 3-D circuit manufacturing. However, there is still a possible barrier of design complexity in exploiting 3-D technologies. This article discusses the impact of migrating from 2-D to 3-D on the difficulty of floorplanning and placement. By looking at a basic formulation of the graph cuboidal dual problem, we show that the 3-D cases and the 3-layer 2.5-D cases are fundamentally more difficult than the 2-D cases in terms of computational complexity. By comparison among these cases, the intrinsic complexity in 3-D floorplan structures is revealed in the hard-to-decide relations between topological connections and geometrical contacts. The results show possible challenges in the future for physical design and CAD of 3-D integrated circuits.
What is the statistical method for at-speed testing?
Authors: Xiong Jinjun
Published: October 2010

Manufacturing testing becomes increasingly difficult in the nanometer manufacturing region because of the impacts of process variation on path delays. It has been frequently observed from manufacturing testing that different chips exhibit different speed limiting paths; and different set of paths may fail to meet the timing specification for different chips.
What is process window?
Authors: Gupta Puneet
Published: October 2010

Process window is a collection of values of process parameters that allow circuit to be manufactured and to operate under desired specifications. For instance, lithographic process window is typically defined as the set of {focus, exposure} points to control critical dimension (CD) variation to within 10%. One simple way visualizing it is using a Focus-Exposure Matrix (FEM) curve which plots exposure vs. defocus for a given linewidth tolerance. Maximal inscribed rectangle in this plot then represents the process window [1]. Of course, metrics can go beyond linewidth (e.g., sidewall angle) as can process variables (e.g., overlay, temperature). Furthermore, the overall process window for a design will be intersection or overlap of process windows for all different layout patterns existing in the design (e.g., isolated vs. dense lines) [2].
Temporal response of canine flexor tendon to limb suspension
Authors: Sun Yu-Long , Thoreson Andrew R. , Cha Stephen S. , Zhao Chunfeng , An Kai-Nan , Amadio Peter C.
Published: October 2010

Tendon disuse, or stress deprivation, frequently accompanies clinical disorders and treatments, yet the metabolism of tendons subject to stress deprivation has rarely been investigated systematically. The effects of stress deprivation on canine flexor tendon were investigated in this study. One adult canine forepaw was suspended for 21 or 42 days. Control forepaws were collected from dogs that had no intervention on their limbs and paws. The expression of collagen I and III was not significantly altered in the tendons disused for 21 days but was significantly decreased at 42 days ( P < 0.03). The expression of collagen II, aggrecan, decorin, and fibronectin was significantly decreased in the tendons in the suspended limbs at 21 days ( P < 0.002) and further reduced at 42 days. With stress deprivation, the expression of matrix metalloproteinase 2 (MMP2) was significantly increased ( P < 0.004) at 21 and 42 days. The expression of MMP3 was significantly decreased at 21 and 42 days ( P < 0.03). The expression of MMP13 was not altered with stress deprivation at 21 and 42 days. The expression of MMP14 was significantly increased at 21 days ( P = 0.0015) and returned to the control level at 42 days. Tissue inhibitor of metalloproteinase 1 (TIMP1) expression was decreased after the limbs were suspended for 42 days ( P = 0.0043), but not 21 days. However, TIMP2 expression was not significantly different from control at 21 or 42 days. Furthermore, the cross-sectional area of the stress-deprived tendons at 42 days was decreased compared with the control group ( P < 0.01). The intervention method in this study did not result in any alteration of stiffness of the tendon. Our study demonstrated that stress deprivation decreases the anabolic process and increases the catabolic process of extracellular matrix in flexor tendon.
Identifiable Cells in the Crustacean Stomatogastric Ganglion
Authors: Hudson Amber E. , Archila Santiago , Prinz Astrid A.
Published: October 2010

Neural circuits rely on slight physiological differences between the component cells for proper function. When any circuit is analyzed, it is important to characterize the features that distinguish one cell type from another. This review describes the methods used to identify the neurons of the crustacean stomatogastric ganglion.
Extraction of Zinc and Manganese from Alkaline and Zinc-Carbon Spent Batteries by Citric-Sulphuric Acid Solution
Authors: Ferella Francesco , De Michelis Ida , Beolchini Francesca , Innocenzi Valentina , Vegliò Francesco
Published: October 2010

The paper is focused on the recovery of zinc and manganese from alkaline and zinc-carbon spent batteries. Metals are extracted by sulphuric acid leaching in the presence of citric acid as reducing agent. Leaching tests are carried out according to a24full factorial design, and empirical equations for Mn and Zn extraction yields are determined from experimental data as a function of pulp density, sulphuric acid concentration, temperature, and citric acid concentration. The highest values experimentally observed for extraction yields were 97% of manganese and 100% of zinc, under the following operating conditions: temperature40∘C, pulp density 20%, sulphuric acid concentration 1.8 M, and citric acid 40 gL-1. A second series of leaching tests is also performed to derive other empirical models to predict zinc and manganese extraction. Precipitation tests, aimed both at investigating precipitation of zinc during leaching and at evaluating recovery options of zinc and manganese, show that a quantitative precipitation of zinc can be reached but a coprecipitation of nearly 30% of manganese also takes place. The achieved results allow to propose a battery recycling process based on a countercurrent reducing leaching by citric acid in sulphuric solution.
Phase-Dependent Color Polyphenism in Field Populations of Red Locust Nymphs (Nomadacris septemfasciataServ.) in Madagascar
Authors: Lecoq Michel , Chamouine Abdou , Luong-Skovmand My-Hanh
Published: October 2010

Pigmentation of the Red locust hopper,Nomadacris septemfasciataServ., was studied in natural conditions in Madagascar in relation to population density. More than one thousand hoppers were collected and described according to a semiquantitative method. A typology is proposed, strictly reflecting the increase in population densities. This correctly translated the progressive evolution of a solitary state into a gregarious state, while passing through several intermediate transiens stages. According to their density, hopper populations consist of a mixture, in various proportions, of several pigment types. The gregarization threshold is estimated at 100,000 hoppers/ha. A slight black spot on the hind femur is the first sign of gregarization. These results should improve the reliability of the information collected by the Malagasy National locust centre when surveying this major pest. They question the rapidity of the gregarization process in natural conditions as well as the stimuli involved.
Sex Chromosome Evolution in Amniotes: Applications for Bacterial Artificial Chromosome Libraries
Authors: Janes Daniel E. , Valenzuela Nicole , Ezaz Tariq , Amemiya Chris , Edwards Scott V.
Published: October 2010

Variability among sex chromosome pairs in amniotes denotes a dynamic history. Since amniotes diverged from a common ancestor, their sex chromosome pairs and, more broadly, sex‐determining mechanisms have changed reversibly and frequently. These changes have been studied and characterized through the use of many tools and experimental approaches but perhaps most effectively through applications for bacterial artificial chromosome (BAC) libraries. Individual BAC clones carry 100–200 kb of sequence from one individual of a target species that can be isolated by screening, mapped onto karyotypes, and sequenced. With these techniques, researchers have identified differences and similarities in sex chromosome content and organization across amniotes and have addressed hypotheses regarding the frequency and direction of past changes. Here, we review studies of sex chromosome evolution in amniotes and the ways in which the field of research has been affected by the advent of BAC libraries.
T-Cell Traffic Jam in Hodgkin's Lymphoma: Pathogenetic and Therapeutic Implications
Authors: Fozza Claudio , Longinotti Maurizio
Published: October 2010

In hematologic malignancies, the microenvironment is often characterized by nonneoplastic cells with peculiar phenotypic and functional features. This is particularly true in Hodgkin's lymphoma (HL), in which T lymphocytes surrounding Hodgkin's Reed-Sternberg cells are essentially polarized towards a memory T-helper type 2 phenotype. In this paper we will first evaluate the main processes modulating T-cell recruitment towards the lymph node microenvironment in HL, especially focusing on the role played by cytokines. We will then consider the most relevant mechanisms of immune escape exerted by neoplastic cells in order to evade antitumor immunity. The potential pathogenetic and prognostic impact of regulatory T cells in such a context will be also described. We will finally overview some of the strategies of cellular immunotherapy applied in patients with HL.
Anhedonia and Pessimism in Hospitalized Depressed Adolescents
Authors: Gutkovich Zinoviy , Morrissey Richard F. , Espaillat Ricardo K. , Dicker Robert
Published: October 2010

This longitudinal study investigates whether anhedonia and pessimistic attributional style represent a clinical state or a trait in hospitalized depressed adolescents. 81 consecutive adolescent inpatients were screened with the Beck Depression Inventory (BDI) and the clinician-rated Major Depressive Disorder (MDD) criteria sheet. 51 patients with BDI score≥10and/or≥4symptoms on MDD criteria sheet were assessed at Time 1 upon admission, with 39 patients (78%) assessed at discharge (Time 2) with the Pleasure Scale for Children and Children's Attributional Style Questionnaire—Revised. Anhedonia and pessimism at admission were associated with BDI scores at admission and discharge as well as number of depressive symptoms and depression severity. MDD diagnosis was associated with anhedonia, but not with pessimism. Pessimism—but not anhedonia—improved significantly by discharge. Results suggest that while some adolescents exhibit enduring anhedonia, pessimistic attributional style appears to be a concomitant feature of an acute depressive state.
Integrative Genomics Analyses Reveal Molecularly Distinct Subgroups of B-Cell Chronic Lymphocytic Leukemia Patients with 13q14 Deletion
Authors: Mosca Laura , Fabris Sonia , Lionetti Marta , Todoerti Katia , Agnelli Luca , Morabito Fortunato , Cutrona Giovanna , Andronache Adrian , Matis Serena , Ferrari Francesco , Gentile Massimo , Spriano Mauro , Callea Vincenzo , Festini Gianluca , Molica Stefano , Deliliers Giorgio Lambertenghi , Bicciato Silvio , Ferrarini Manlio , Neri Antonino
Published: October 2010

Purpose: Chromosome 13q14 deletion occurs in a substantial number of chronic lymphocytic leukemia (CLL) patients and it is believed to play a pathogenetic role. The exact mechanisms involved in this lesion have not yet been fully elucidated because of its heterogeneity and the imprecise knowledge of the implicated genes. This study was addressed to further contribute to the molecular definition of this lesion in CLL.

Experimental Design: We applied single-nucleotide polymorphism (SNP)-array technology and gene expression profiling data to investigate the 13q14 deletion occurring in a panel of 100 untreated, early-stage (Binet A) patients representative of the major genetics, molecular, and biological features of the disease.

Results: Concordantly with FISH analysis, SNP arrays identified 44 patients with del(13)(q14) including 11 cases with a biallelic deletion. The shorter monoallelic deletion was 635-kb long. The loss of the miR-15a/16-1 cluster occurred in all del(13)(q14) cases except in 2 patients with a monoallelic deletion, who retained both copies. MiR-15a/16 expression was significantly downregulated only in patients with the biallelic loss of the miRNA cluster compared to 13q normal cases. Finally, the natural grouping of SNP profiles by nonnegative matrix factorization algorithm showed that patients could be classified into 2 separate clusters, mainly characterized by short/biallelic versus wide/monoallelic 13q14 deletions. Supervised analyses of expression data showed that specific transcriptional profiles are correlated with these 2 genomic subgroups.

Conclusions: Overall, our data highlight the presence of 2 distinct molecular types of 13q14 deletions, which may be of clinical relevance in CLL. Clin Cancer Res; 16(23); 5641–53. ©2010 AACR.
Percutaneous Cholecystostomy in Critically Ill Patients with a Cholecystitis: A Safe Option
Authors: Koebrugge B. , van Leuken M. , Ernst M.F. , van Munster I. , Bosscha K.
Published: October 2010

Background: Cholecystectomy is the standard procedure in patients with acute cholecystitis. However, some patients might not be able to undergo immediate surgery because of severe sepsis or underlying comorbid conditions. Percutaneous cholecystostomy is a minimally invasive radiological procedure under local anesthesia which seems to be an effective alternative to conservative treatment or immediate laparoscopic/open cholecystectomy. Methods: We retrospectively analyzed 35 patients who underwent percutaneous cholecystostomy between 2003 and 2009. Results: Percutaneous cholecystostomy was technically successful in all patients. Symptoms resolved within 3 days in 33/35 patients. Two patients needed an emergency laparotomy. The catheter dislodged in 5 patients and was replaced in 2/5. The 30-day mortality rate was 3/35 (8.7%) due to gallbladder necrosis, myocardial infarction and multiorgan failure. Median length of hospital stay was 17 days and median drainage time was 28 days. 23 patients (66%) underwent open or laparoscopic cholecystectomy after a median interval of 44 days. Conclusion: Percutaneous cholecystostomy is an effective procedure and a good alternative for patients unfit to undergo immediate surgery because of severe sepsis or underlying comorbid conditions, preferably followed by interval cholecystectomy to prevent recurrent cholecystitis.
Predictive Factors Associated with the Period of Time before Initiation of Hemodialysis in CKD Stages 4 and 5
Authors: Furukawa Masako , Io Hiroaki , Tanimoto Mitsuo , Hagiwara Shinji , Horikoshi Satoshi , Tomino Yasuhiko
Published: October 2010

Background: A majority of patients with chronic kidney disease (CKD) have cardiovascular disease at the initiation of dialysis therapy, suggesting that periodic echocardiographic examinations are important in such patients. The purpose of the present study was to evaluate the correlation between echocardiographic parameters and period of time before initiation of hemodialysis (iHD) in patients with CKD. Methods: 140 patients with CKD stages 4 and 5 were enrolled. They were divided into diabetes and nondiabetes groups. Cardiac predictive parameters for the period of time before iHD were investigated in the patients using univariate and multivariate regression analyses. Results: In the nondiabetes group, systolic blood pressure (SBP) and left atrial volume index (LAVi) were identified as independent risk factors for the period of time before iHD by multivariate regression analysis. Serum albumin level was identified as an independent risk factor in the diabetes group. SBP, LAVi and serum albumin level were identified as independent risk factors in the combined diabetes and nondiabetes groups. Conclusion: LAVi measurements during echocardiography, together with SBP and serum albumin levels, may be useful predictive factors for the period of time before iHD in patients with CKD stages 4 and 5.
Africa and Nephrology: The Forgotten Continent
Authors: Katz Ivor J. , Gerntholtz Trevor , Naicker Sarala
Published: October 2010

Chronic kidney disease (CKD) is not a priority on the health agenda in Africa and it remains a ‘forgotten condition’. Most people in Africa do not have access to dialysis or transplantation, if they develop end-stage renal disease. Cardiovascular disease (CVD) and HIV/AIDS enjoy a more prominent profile as a serious cause of morbidity and mortality, but despite the clear links of CVD and HIV with CKD, there has been a failure to highlight the link between chronic illnesses like diabetes, hypertension and HIV/AIDS and both CKD and CVD. Management of chronic illnesses requires a functioning public health system and good links between primary and specialist care. Despite calls to establish CKD prevention programs, there are very few in Africa and they have not been integrated into existing primary healthcare systems. This is aggravated by shortages of both financial and human resources and failure to strengthen health systems managing chronic diseases. The result is that very few people in Africa with CKD are managed early or receive dialysis or transplantation. This article investigates some of the issues impacting on the recognition of CKD as a public health issue, and will also consider some factors which could make CKD a more prominent chronic disease in Africa.
Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children
Authors: Frontroth Juan Pablo , Hepner Mirta , Sciuccati Gabriela , Torres Aurora Feliú , Pieroni Graciela , Bonduel Mariana
Published: October 2010

Type 2B von Willebrand disease (VWD2B) and platelet-type von Wille-brand disease (PT-VWD) are rare bleeding disorders characterised by an increased ristocetin-induced platelet aggregation (RIPA) at low dose of ristocetin. It was the objective of this study to detect children with VWD2B and PT-VWD using RIPA at low dose of ristocetin (0.5 mg/ml) in the screening evaluation of bleeding disorders, and to analyse the phenotypic data along with the molecular findings. Over a 14-year period, 641 children with personal and family bleeding symptoms or bleeding from birth with previously uncharacterised haemostatic disorders were prospectively studied. Six unrelated patients (0.93%) showed RIPA at low dose of ristocetin. RIPA-based mixing studies identified that the plasma of the six probands and at least one parent from five unrelated families induced aggregation of normal platelets with the addition of low-dose ristocetin. None of the probands’ platelets showed aggre-gation with cryoprecipitate. Low ristocetin cofactor activity/VWF antigen ratio with absent collagen binding activity or thrombocytopenia were detected respectively in only two patients. Molecular analysis of exon 28 of the VWF gene identified mutations in only three patients. No mutation in the GP1BA gene was found. In this large prospective paediatric study, the screening approach including RIPA at low dose of ristocetin permitted the detection of patients with VWD2B that would otherwise have been missed. No patient with phenotype or genotype of PT-VWD was identified. Heterogeneity of bleeding symptoms and phenotypic parameters were found among members of the same family.
Efficacy of prothrombin complex concentrate to reverse the anticoagulant effect of the pentasaccharide fondaparinux in a rabbit model
Authors: Durand Marion , Emmerich Joseph , Dizier Blandine , Lecompte Thomas , Samama Charles-Marc , Godier Anne
Published: October 2010

As a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg−1] and saline), PCC (fondaparinux and PCC [40 UI.kg−1]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelasto-metric parameters (ROTEM®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.
Increase in GLUT1 in Smooth Muscle Alters Vascular Contractility and Increases Inflammation in Response to Vascular Injury
Authors: Adhikari Neeta , Basi David L. , Carlson Marjorie , Mariash Ami , Hong Zhigang , Lehman Ute , Mullegama Sureni , Weir Edward K. , Hall Jennifer L.
Published: October 2010

Objective—

The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease.

Methods and Results—

A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non–insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3,
P
<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10,
P
<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4,
P
<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4,
P
<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4,
P
<0.003).

Conclusion—

In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-β activity.
p53 Impairs Endothelial Function by Transcriptionally Repressing Kruppel-Like Factor 2
Authors: Kumar Ajay , Kim Cuk-Seong , Hoffman Timothy A. , Naqvi Asma , DeRicco Jeremy , Jung Saet-Byel , Lin Zhiyong , Jain Mukesh K. , Irani Kaikobad
Published: October 2010

Objective—

To evaluate if p53 decreases Kruppel-Like Factor 2 (KLF2) expression and determine whether p53-mediated suppression of KLF2 plays a role in p53-induced endothelial dysfunction.

Methods and Results—

Endothelial KLF2 mediates endothelium-dependent vascular homeostasis by differentially regulating endothelial genes, leading to an anti-inflammatory and antithrombotic endothelial surface with normal vasodilatory function. In contrast, the tumor suppressor p53 leads to inflammatory gene expression and impairs endothelium-dependent vasodilatation, thus promoting endothelial dysfunction. The effect of p53 on KLF2 expression was determined. p53 inhibited KLF2 transcription in a histone deacetylase–dependent and a histone acetyltransferase–independent fashion. KLF2 expression was suppressed by p53 via a conserved p53-binding repressor sequence in its promoter. p53 bound to, and stimulated, deacetylation of Histone H3 at the KLF2 promoter. The effect of p53 on endothelial KLF2 target genes was examined. Downregulation of p53 increased expression of endothelial NO synthase and thrombomodulin and inhibited expression of plasminogen activator inhibitor 1. Conversely, overexpression of p53 suppressed endothelial NO synthase and thrombomodulin expression and stimulated plasminogen activator inhibitor 1 and endothelin-1 expression. Knockdown of KLF2 abolished the p53-induced decrease in thrombomodulin and increase in endothelin-1. Both, overexpression of p53 and knockdown of KLF2 in endothelial cells increased blood coagulation on an endothelial cell monolayer. The p53-induced increase in coagulation was rescued by forced expression of KLF2. p53 also impaired endothelium-dependent vasodilatation and decreased bioavailable vascular NO, both of which were rescued by forced KLF2 expression.

Conclusion—

These findings illustrate a novel p53-dependent mechanism for the regulation of endothelial KLF2 expression. In addition, they show that downregulation of KLF2, in part, mediates a p53-stimulated dysfunctional endothelium.
Determinants of Postinfarction Ventricular Tachycardia
Authors: Crawford Thomas , Cowger Jennifer , Desjardins Benoit , Kim Hyungjin Myra , Good Eric , Jongnarangsin Krit , Oral Hakan , Chugh Aman , Pelosi Frank , Morady Fred , Bogun Frank
Published: October 2010

Background—

Structural factors contributing to the development of postinfarction ventricular tachycardia (VT) are unclear. The purpose of this study was to analyze infarct architecture and electrogram characteristics in patients with and without inducible VT and to identify correlates of postinfarction VT.

Methods and Results—

Twenty-four postinfarction patients (median age, 64 [53, 70] years) were referred for radiofrequency catheter ablation of VT (n=12) or frequent symptomatic premature ventricular contractions (PVCs) (n=12). Delayed-enhanced (DE) MRI was obtained before ablation. Electroanatomical mapping was performed and scar area and electrogram characteristics of the scar tissue compared in patients with and without inducible VT.

The median ejection fraction in patients with and without inducible VT was 27% (22%, 43%) and 43% (40%, 47%), respectively (
P
=0.085). Subendocardial infarct area determined by DE-MRI was larger in patients with inducible VT (43 [38, 62] cm
2
) than in those with noninducible VT (8 [4, 11] cm
2
;
P
=0.002), and unipolar and bipolar voltages on electroanatomical maps were significantly lower in patients with inducible VT (both
P
<0.05). An infarct volume of >14% identified 11 of 12 patients with inducible VT (area under the curve, 0.94;
P
=0.007). On electroanatomical mapping, distinct sites with isolated potentials (IPs) were more prevalent in patients with inducible VT than in those without (13.2% versus 1.1% of points within scar;
P
<0.001). The number of inducible VTs correlated with the number of distinct sites with IPs (
R
=0.87;
P
<0.0001).

Conclusions—

Scar tissue in postinfarction patients with inducible VT shows quantitative and qualitative differences from scars in patients without inducible VT. Scar size and IPs are correlated with VT inducibility.
Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes
Authors: Hariharan Nirmala , Maejima Yasuhiro , Nakae Jun , Paik Jihye , DePinho Ronald A. , Sadoshima Junichi
Published: October 2010

Rationale:

Autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood.

Objective:

We investigated the role of FoxOs and its posttranslational modification in mediating starvation-induced autophagy.

Methods and Results:

Glucose deprivation (GD) increased autophagic flux in cultured CMs, as evidenced by increased mRFP-GFP-LC3 puncta and decreases in p62, which was accompanied by upregulation of Sirt1 and FoxO1. Overexpression of either Sirt1 or FoxO1 was sufficient for inducing autophagic flux, whereas both Sirt1 and FoxO1 were required for GD-induced autophagy. GD increased deacetylation of FoxO1, and Sirt1 was required for GD-induced deacetylation of FoxO1. Overexpression of FoxO1(3A/LXXAA), which cannot interact with Sirt1, or p300, a histone acetylase, increased acetylation of FoxO1 and inhibited GD-induced autophagy. FoxO1 increased expression of Rab7, a small GTP-binding protein that mediates late autophagosome–lysosome fusion, which was both necessary and sufficient for mediating FoxO1-induced increases in autophagic flux. Although cardiac function was maintained in control mice after 48 hours of food starvation, it was significantly deteriorated in mice with cardiac-specific overexpression of FoxO1(3A/LXXAA), those with cardiac-specific homozygous deletion of FoxO1 (c-FoxO1
−/−
), and
beclin1
+/−
mice, in which autophagy is significantly inhibited.

Conclusions:

These results suggest that Sirt1-mediated deacetylation of FoxO1 and upregulation of Rab7 play an important role in mediating starvation-induced increases in autophagic flux, which in turn plays an essential role in maintaining left ventricular function during starvation.
MicroRNA-218 Regulates Vascular Patterning by Modulation of Slit-Robo Signaling
Authors: Small Eric M. , Sutherland Lillian B. , Rajagopalan Kartik N. , Wang Shusheng , Olson Eric N.
Published: October 2010

Rationale:

Establishment of a functional vasculature requires the interconnection and remodeling of nascent blood vessels. Precise regulation of factors that influence endothelial cell migration and function is essential for these stereotypical vascular patterning events. The secreted Slit ligands and their Robo receptors constitute a critical signaling pathway controlling the directed migration of both neurons and vascular endothelial cells during embryonic development, but the mechanisms of their regulation are incompletely understood.

Objective:

To identify microRNAs regulating aspects of the Slit-Robo pathway and vascular patterning.

Methods and Results:

Here, we provide evidence that microRNA (miR)-218, which is encoded by an intron of the
Slit
genes, inhibits the expression of Robo1 and Robo2 and multiple components of the heparan sulfate biosynthetic pathway. Using in vitro and in vivo approaches, we demonstrate that miR-218 directly represses the expression of Robo1, Robo2, and glucuronyl C5-epimerase (GLCE), and that an intact miR-218–Slit–Robo regulatory network is essential for normal vascularization of the retina. Knockdown of miR-218 results in aberrant regulation of this signaling axis, abnormal endothelial cell migration, and reduced complexity of the retinal vasculature.

Conclusions:

Our findings link Slit gene expression to the posttranscriptional regulation of Robo receptors and heparan sulfate biosynthetic enzymes, allowing for precise control over vascular guidance cues influencing the organization of blood vessels during development.
Radiofrequency Catheter Ablation of Atrial Fibrillation: A Cause of Silent Thromboembolism?
Authors: Gaita Fiorenzo , Caponi Domenico , Pianelli Martina , Scaglione Marco , Toso Elisabetta , Cesarani Federico , Boffano Carlo , Gandini Giovanni , Valentini Maria Consuelo , De Ponti Roberto , Halimi Franck , Leclercq Jean François
Published: October 2010

Background—

Radiofrequency left atrial catheter ablation has become a routine procedure for treatment of atrial fibrillation. The aim of this study was to assess with preprocedural and postprocedural cerebral magnetic resonance imaging the thromboembolic risk, either silent or clinically manifest, in the context of atrial fibrillation ablation. The secondary end point was the identification of clinical or procedural parameters that correlate with cerebral embolism.

Methods and Results—

A total of 232 consecutive patients with paroxysmal or persistent atrial fibrillation who were candidates for radiofrequency left atrial catheter ablation were included in the study. Pulmonary vein isolation or pulmonary vein isolation plus linear lesions plus atrial defragmentation with the use of irrigated-tip ablation catheters was performed. All of the patients underwent preprocedural and postablation cerebral magnetic resonance imaging. A periprocedural symptomatic cerebrovascular accident occurred in 1 patient (0.4). Postprocedural cerebral magnetic resonance imaging was positive for new embolic lesions in 33 patients (14). No clinical parameters such as age, hypertension, diabetes mellitus, previous history of stroke, type of atrial fibrillation, and preablation antithrombotic treatment showed significant correlation with ischemic cerebral embolism. Procedural parameters such as activated clotting time value and, in particular, electric or pharmacological cardioversion to sinus rhythm correlated with an increased incidence of cerebral embolism. Cardioversion was also associated with an increased risk of 2.75 (95 confidence interval, 1.29 to 5.89;
P
=0.009).

Conclusions—

Radiofrequency left atrial catheter ablation carries a low risk of symptomatic cerebral ischemia but is associated with a substantial risk of silent cerebral ischemia detected on magnetic resonance imaging. Independent risk factors for cerebral thromboembolism are the level of activated clotting time and, in particular, the electric or pharmacological cardioversion to sinus rhythm during the procedure.