bluuebunny/crossref_metadata_2025 huggingface dataset:
The List-Decoding Size of Fourier-Sparse Boolean Functions
Authors: Haviv Ishay , Regev Oded
Published: May 2016

A function defined on the Boolean hypercube is
k
-
Fourier-sparse
if it has at most
k
nonzero Fourier coefficients. For a function
f
: F
2
n
→ R and parameters
k
and
d
, we prove a strong upper bound on the number of
k
-Fourier-sparse Boolean functions that disagree with
f
on at most
d
inputs. Our bound implies that the number of uniform and independent random samples needed for learning the class of
k
-Fourier-sparse Boolean functions on
n
variables exactly is at most
O
(
n
·
k
log
k
).

As an application, we prove an upper bound on the query complexity of testing Booleanity of Fourier-sparse functions. Our bound is tight up to a logarithmic factor and quadratically improves on a result due to Gur and Tamuz [2013].
On Precision Bound of Distributed Fault-Tolerant Sensor Fusion Algorithms
Authors: Ao Buke , Wang Yongcai , Yu Lu , Brooks Richard R. , Iyengar S. S.
Published: May 2016

Sensors have limited precision and accuracy. They extract data from the physical environment, which contains noise. The goal of sensor fusion is to make the final decision robust, minimizing the influence of noise and system errors. One problem that has not been adequately addressed is establishing the bounds of fusion result precision. Precision is the maximum range of disagreement that can be introduced by one or more faulty inputs. This definition of precision is consistent both with Lamport’s Byzantine Generals problem and the mini-max criteria commonly found in game theory. This article considers the precision bounds of several fault-tolerant information fusion approaches, including Byzantine agreement, Marzullo’s interval-based approach, and the Brooks-Iyengar fusion algorithm. We derive precision bounds for these fusion algorithms. The analysis provides insight into the limits imposed by fault tolerance and guidance for applying fusion approaches to applications.
Cloud Log Forensics
Authors: Khan Suleman , Gani Abdullah , Wahab Ainuddin Wahid Abdul , Bagiwa Mustapha Aminu , Shiraz Muhammad , Khan Samee U. , Buyya Rajkumar , Zomaya Albert Y.
Published: May 2016

Cloud log forensics (CLF) mitigates the investigation process by identifying the malicious behavior of attackers through profound cloud log analysis. However, the accessibility attributes of cloud logs obstruct accomplishment of the goal to investigate cloud logs for various susceptibilities. Accessibility involves the issues of cloud log access, selection of proper cloud log file, cloud log data integrity, and trustworthiness of cloud logs. Therefore, forensic investigators of cloud log files are dependent on cloud service providers (CSPs) to get access of different cloud logs. Accessing cloud logs from outside the cloud without depending on the CSP is a challenging research area, whereas the increase in cloud attacks has increased the need for CLF to investigate the malicious activities of attackers. This paper reviews the state of the art of CLF and highlights different challenges and issues involved in investigating cloud log data. The logging mode, the importance of CLF, and cloud log-as-a-service are introduced. Moreover, case studies related to CLF are explained to highlight the practical implementation of cloud log investigation for analyzing malicious behaviors. The CLF security requirements, vulnerability points, and challenges are identified to tolerate different cloud log susceptibilities. We identify and introduce challenges and future directions to highlight open research areas of CLF for motivating investigators, academicians, and researchers to investigate them.
A formalization of typed lua
Authors: Maidl André Murbach , Mascarenhas Fabio , Ierusalimschy Roberto
Published: May 2016

Programmers often migrate from a dynamically typed to a statically typed language when their simple scripts evolve into complex programs. Optional type systems are one way of having both static and dynamic typing in the same language, while keeping its dynamically typed semantics. This makes evolving a program from dynamic to static typing a matter of describing the implied types that it is using and adding annotations to make those types explicit. Designing an optional type system for an existing dynamically typed language is challenging, as its types should feel natural to programmers that are already familiar with this language. In this work, we give a formal description of Typed Lua, an optional type system for Lua, with a focus on two of its novel type system features: incremental evolution of imperative record and object types that is both lightweight and type-safe, and projection types, a combination of flow typing, functions that return multiple values, and multiple assignment. While our type system is tailored to the features and idioms of Lua, its features can be adapted to other imperative scripting languages.
Message safety in Dart
Authors: Ernst Erik , Møller Anders , Schwarz Mathias , Strocco Fabio
Published: May 2016

Unlike traditional static type checking, the type system in the Dart programming language is unsound by design, even for fully annotated programs. The rationale has been that this allows compile-time detection of likely errors and enables code completion in integrated development environments, without being restrictive on programmers. Despite unsoundness, judicious use of type annotations can ensure useful properties of the runtime behavior of Dart programs. We present a formal model of a core of Dart with a focus on its type system, which allows us to elucidate the causes of unsoundness. Our main contribution is a characterization of message-safe programs and a theorem stating that such programs will never encounter 'message not understood' errors at runtime. Message safety is less restrictive than traditional type soundness, and we argue that it forms a natural intermediate point between dynamically typed and statically typed Dart programs.
Compiling for multi-language task migration
Authors: Feeley Marc
Published: May 2016

Task migration allows a running program to continue its execution in a different destination environment. Increasingly, execution environments are defined by combinations of cultural and technological constraints, affecting the choice of host language, libraries and tools. A compiler supporting multiple target environments and task migration must be able to marshal continuations and then unmarshal and continue their execution, ideally, even if the language of the destination environment is different. In this paper, we propose a compilation approach based on a virtual machine that strikes a balance between implementation portability and efficiency. We explain its implementation within a Scheme compiler targeting JavaScript, PHP, Python, Ruby and Java -- some of the most popular host languages for web applications. As our experiments show, this approach compares well with other Scheme compilers targeting high-level languages in terms of execution speed, being sometimes up to 3 orders of magnitude faster.
Java-to-JavaScript translation via structured control flow reconstruction of compiler IR
Authors: Leopoldseder David , Stadler Lukas , Wimmer Christian , Mössenböck Hanspeter
Published: May 2016

We present an approach to cross-compile Java bytecodes to Java-Script, building on existing Java optimizing compiler technology. Static analysis determines which Java classes and methods are reachable. These are then translated to JavaScript using a re-configured Java just-in-time compiler with a new back end that generates JavaScript instead of machine code. Standard compiler optimizations such as method inlining and global value numbering, as well as advanced optimizations such as escape analysis, lead to compact and optimized JavaScript code. Compiler IR is unstructured, so structured control flow needs to be reconstructed before code generation is possible. We present details of our control flow reconstruction algorithm. Our system is based on Graal, an open-source optimizing compiler for the Java HotSpot VM and other VMs. The modular and VM-independent architecture of Graal allows us to reuse the intermediate representation, the bytecode parser, and the high-level optimizations. Our custom back end first performs control flow reconstruction and then JavaScript code generation. The generated JavaScript undergoes a set of optimizations to increase readability and performance. Static analysis is performed on the Graal intermediate representation as well. Benchmark results for medium-sized Java benchmarks such as SPECjbb2005 run with acceptable performance on the V8 JavaScript VM.
Measuring polymorphism in python programs
Authors: Åkerblom Beatrice , Wrigstad Tobias
Published: May 2016

Following the increased popularity of dynamic languages and their increased use in critical software, there have been many proposals to retrofit static type system to these languages to improve possibilities to catch bugs and improve performance. A key question for any type system is whether the types should be structural, for more expressiveness, or nominal, to carry more meaning for the programmer. For retrofitted type systems, it seems the current trend is using structural types. This paper attempts to answer the question to what extent this extra expressiveness is needed, and how the possible polymorphism in dynamic code is used in practise. We study polymorphism in 36 real-world open source Python programs and approximate to what extent nominal and structural types could be used to type these programs. The study is based on collecting traces from multiple runs of the programs and analysing the polymorphic degrees of targets at more than 7 million call-sites. Our results show that while polymorphism is used in all programs, the programs are to a great extent monomorphic. The polymorphism found is evenly distributed across libraries and program-specific code and occur both during program start-up and normal execution. Most programs contain a few ``megamorphic'' call-sites where receiver types vary widely. The non-monomorphic parts of the programs can to some extent be typed with nominal or structural types, but none of the approaches can type entire programs.
Tracking down performance variation against source code evolution
Authors: Alcocer Juan Pablo Sandoval , Bergel Alexandre
Published: May 2016

Little is known about how software performance evolves across software revisions. The severity of this situation is high since (i) most performance variations seem to happen accidentally and (ii) addressing a performance regression is challenging, especially when functional code is stacked on it. This paper reports an empirical study on the performance evolution of 19 applications, totaling over 19 MLOC. It took 52 days to run our 49 benchmarks. By relating performance variation with source code revisions, we found out that: (i) 1 out of every 3 application revisions introduces a performance variation, (ii) performance variations may be classified into 9 patterns, (iii) the most prominent cause of performance regression involves loops and collections. We carefully describe the patterns we identified, and detail how we addressed the numerous challenges we faced to complete our experiment.
Generating reactive programs for graphical user interfaces from multi-way dataflow constraint systems
Authors: Foust Gabriel , Järvi Jaakko , Parent Sean
Published: May 2016

For a GUI to remain responsive, it must be able to schedule lengthy tasks to be executed asynchronously. In the traditional approach to GUI implementation--writing functions to handle individual user events--asynchronous programming easily leads to defects. Ensuring that all data dependencies are respected is difficult when new events arrive while prior events are still being handled. Reactive programming techniques, gaining popularity in GUI programming, help since they make data dependencies explicit and enforce them automatically as variables' values change. However, data dependencies in GUIs usually change along with its state. Reactive programming must therefore describe a GUI as a collection of many reactive programs, whose interaction the programmer must explicitly coordinate. This paper presents a declarative approach for GUI programming that relieves the programmer from coordinating asynchronous computations. The approach is based on our prior work on "property models", where GUI state is maintained by a dataflow constraint system. A property model responds to user events by atomically constructing new data dependencies and scheduling asynchronous computations to enforce those dependencies. In essence, a property model dynamically generates a reactive program, adding to it as new events occur. The approach gives the following guarantee: the same sequence of events produces the same results, regardless of the timing of those events.
Shallow embedding of DSLs via online partial evaluation
Authors: Leißa Roland , Boesche Klaas , Hack Sebastian , Membarth Richard , Slusallek Philipp
Published: May 2016

This paper investigates shallow embedding of DSLs by means of online partial evaluation. To this end, we present a novel online partial evaluator for continuation-passing style languages. We argue that it has, in contrast to prior work, a predictable termination policy that works well in practice. We present our approach formally using a continuation-passing variant of PCF and prove its termination properties. We evaluate our technique experimentally in the field of visual and high-performance computing and show that our evaluator produces highly specialized and efficient code for CPUs as well as GPUs that matches the performance of hand-tuned expert code.
Native-2-native: automated cross-platform code synthesis from web-based programming resources
Authors: Byalik Antuan , Chadha Sanchit , Tilevich Eli
Published: May 2016

For maximal market penetration, popular mobile applications are typically supported on all major platforms, including Android and iOS. Despite the vast differences in the look-and-feel of major mobile platforms, applications running on these platforms in essence provide the same core functionality. As an application is maintained and evolved, the resulting changes must be replicated on all the supported platforms, a tedious and error-prone programming process. Existing automated source-to-source translation tools prove inadequate due to the structural and idiomatic differences in how functionalities are expressed across major platforms. In this paper, we present a new approach---Native-2-Native---that automatically synthesizes code for a mobile application to make use of native resources on one platform, based on the equivalent program transformations performed on another platform. First, the programmer modifies a mobile application's Android version to make use of some native resource, with a plugin capturing code changes. Based on the changes, the system then parameterizes a web search query over popular programming resources (e.g., Google Code, StackOverflow, etc.), to discover equivalent iOS code blocks with the closest similarity to the programmer-written Android code. The discovered iOS code block is then presented to the programmer as an automatically synthesized Swift source file to further fine-tune and subsequently integrate in the mobile application's iOS version. Our evaluation, enhancing mobile applications to make use of common native resources, shows that the presented approach can correctly synthesize more than 86% of Swift code for the subject applications' iOS versions.
Addressing metamodel revisions in model-based software product lines
Authors: Font Jaime , Arcega Lorena , Haugen Øystein , Cetina Carlos
Published: May 2016

Metamodels evolve over time, which can break the conformance between the models and the metamodel. Model migration strategies aim to co-evolve models and metamodels together, but their application is not fully automatizable and is thus cumbersome and error prone. We introduce the Variable MetaModel (VMM) strategy to address the evolution of the reusable model assets of a model-based Software Product Line. The VMM strategy applies variability modeling ideas to express the evolution of the metamodel in terms of commonalities and variabilities. When the metamodel evolves, the models continue to conform to the VMM, avoiding the need for migration. We have applied both the traditional migration strategy and the VMM strategy to a retrospective case study that includes 13 years of evolution of our industrial partner, an induction hobs manufacturer. The comparison between the two strategies shows better results for the VMM strategy in terms of model indirection, automation, and trust leak.
Towards tool support for spreadsheet-based domain-specific languages
Authors: Adam Sorin , Schultz Ulrik Pagh
Published: May 2016

Spreadsheets are commonly used by non-programmers to store data in a structured form, this data can in some cases be considered to be a program in a domain-specific language (DSL). Unlike ordinary text-based domain-specific languages, there is however currently no formalism for expressing the syntax of such spreadsheet-based DSLs (SDSLs), and there is no tool support for automatically generating language infrastructure such as parsers and IDE support. In this paper we define a simple notion of two-dimensional grammars for SDSLs, and show how such grammars can be used for automatically generating parsers that extract structured data from a spreadsheet in the form of an AST. We demonstrate automatic generation of parsers for a number of examples, including the questionnaire DSL from LWC2014 and a DSL for writing safety specifications.
Lightweight, generative variant exploration for high-performance graphics Applications
Authors: Selgrad Kai , Lier Alexander , Köferl Franz , Stamminger Marc , Lohmann Daniel
Published: May 2016

Rendering performance is an everlasting goal of computer graphics and significant driver for advances in both, hardware architecture and algorithms. Thereby, it has become possible to apply advanced computer graphics technology even in low-cost embedded appliances, such as car instruments. Yet, to come up with an efficient implementation, developers have to put enormous efforts into hardware/problem-specific tailoring, fine-tuning, and domain exploration, which requires profound expert knowledge. If a good solution has been found, there is a high probability that it does not work as well with other architectures or even the next hardware generation. Generative DSL-based approaches could mitigate these efforts and provide for an efficient exploration of algorithmic variants and hardware-specific tuning ideas. However, in vertically organized industries, such as automotive, suppliers are reluctant to introduce these techniques as they fear loss of control, high introduction costs, and additional constraints imposed by the OEM with respect to software and tool-chain certification. Moreover, suppliers do not want to share their generic solutions with the OEM, but only concrete instances. To this end, we propose a light-weight and incremental approach for meta programming of graphics applications. Our approach relies on an existing formulation of C-like languages that is amenable to meta programming, which we extend to become a lightweight language to combine algorithmic features. Our method provides a concise notation for meta programs and generates easily sharable output in the appropriate C-style target language.
Analysing the Kconfig semantics and its analysis tools
Authors: El-Sharkawy Sascha , Krafczyk Adam , Schmid Klaus
Published: May 2016

The Linux kernel is often used as a real world case study to demonstrate novel Software Product Line Engineering research methods. An important point in this is often the analysis of the Kconfig semantics. However, we detected that the semantics of Kconfig is rather unclear and has many special cases, which are not documented in its short specification. We performed a systematic analysis to uncover the correct behaviour of Kconfig and present the results, which are necessary for applying semantically correct analyses. Further, we analyse existing analysis tools of the research community whether they are aware of the correct semantics of Kconfig. These analyses can be used for improving existing analysis tools as well as decision support for selecting an appropriate tool for a specific analysis. In summary we contribute to a better understanding of Kconfig in the research community to improve the validity of evaluations based on Linux.
Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance
Authors: Ilan Yaron
Published: May 2016

The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.
Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor
Authors: Bonnevaux Hélène , Lemaitre Olivier , Vincent Loic , Levit Mikhail N. , Windenberger Fanny , Halley Frank , Delorme Cécile , Lengauer Christoph , Garcia-Echeverria Carlos , Virone-Oddos Angela
Published: May 2016

Class IA PI3K pathway activation resulting from PTEN deficiency has been associated with lack of sensitivity of melanoma to BRAF kinase inhibitors. Although previous studies have shown synergistic activity when pan-PI3K inhibitors were combined with MAPK inhibitors in the treatment of melanoma exhibiting concurrent genetic abnormalities, overlapping adverse events in patients limit optimal dosing and clinical application. With the aim of specifically targeting PTEN-deficient cancers and minimizing the potential for on-target toxicity when inhibiting multiple PI3K isoforms, we developed a program to discover PI3Kβ-selective kinase inhibitors and identified SAR260301 as a potent PI3Kβ-selective, orally available compound, which is now in clinical development. Herein, we provide a detailed biological characterization of SAR260301, and show that this compound has outstanding biochemical and cellular selectivity for the PI3Kβ isoform versus the α, δ, and γ isoforms and a large panel of protein and lipid kinases. We demonstrate that SAR260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models, and has synergistic antitumor activity when combined with vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models. Combination treatments were very well tolerated, suggesting the potential for a superior safety profile at optimal dosing using selective compounds to inhibit multiple signaling pathways. Together, these experiments provide a preclinical proof-of-concept for safely combining inhibitors of PI3Kβ and BRAF or MEK kinase modulators to improve antitumor activity in PTEN-deficient/BRAF-mutant melanoma, and support the evaluation of SAR260301-based combinations in clinical studies. Mol Cancer Ther; 15(7); 1460–71. ©2016 AACR.
Belastungstests bei pulmonal-arterieller Hypertonie
Authors: Provencher Steeve , Mainguy Vincent
Published: May 2016

Die pulmonal-arterielle Hypertonie (PAH) manifestiert sich am stärksten in der Dyspnoe, Belastungsintoleranz und verminderten Lebensqualität. Die Mechanismen der Belastungsintoleranz bei PAH sind eindeutig multifaktoriell und umfassen kardiale, respiratorische und peripher-muskuläre Anomalien. Die Belastungskapazität ist somit ein Marker der integrierten Reaktion aller am O2-Transport und -Verbrauch beteiligten Systeme. Daher ist die objektive Messung der Belastungskapazität eine sinnvolle und relevante Maßnahme zur Beurteilung von PAH-Patienten, da sie eine Orientierung bezüglich der Schwere und des Verlaufs der Erkrankung sowie des Ansprechens auf die Therapie ermöglicht. Im Laufe der Jahre nahm die Messung der Belastungskapazität daher eine zentrale Rolle in der Patientenevaluation sowohl in klinischen Studien als auch in PAH-Kliniken ein. Ihre Responsivität auf pharmakologische Interventionen ermöglichte auch den Wirksamkeitsnachweis neuer PAH-spezifischer Therapien. Jedoch ist ihre Sensitivität zum Nachweis von Verbesserungen nach Therapiemaßnahmen jedoch in aktuellen Kombinationsstudien sowie bei Patienten mit weniger schwerer Erkrankung in Frage gestellt worden. Die Zuverlässigkeit von Belastungstests bei nicht idiopathischer PAH muss ebenfalls noch validiert werden. Diese Arbeit befasst sich mit der Physiopathologie der körperlichen Belastung und der klinischen Rele- vanz von Belastungstests bei PAH.
Respiratorische Auswirkungen einer adaptiven Servoventilationstherapie bei Patienten mit Herzinsuffizienz und Cheyne-Stokes-Atmung im Vergleich zu gesunden Probanden
Authors: Herkenrath Simon-Dominik
Published: May 2016

Hintergrund: Die Behandlung mittels adaptiver Servoventilation (ASV) im Schlaf wird häufig zur Behandlung von Cheyne-Stokes-Atmung (CSR) eingesetzt, einer bei Patienten mit moderater bis schwerer Herzinsuffizienz (HI) sehr verbreiteten Form der periodischen Atmung (Hyperventilation). Ziele: Wir analysierten und verglichen in dieser Studie die akuten Auswirkungen eines neuartigen ASV-Systems auf den Kohlendioxiddruck (pCO2) und die Sauerstoffsättigung (SaO2) bei HI-Patienten mit CSR und bei gesunden Probanden. Zusätzlich wurde untersucht, welchen Einfluss der Schlaf und Wachzustand auf den ASV-Algorithmus hat. Methoden: Alle Teilnehmer unterzogen sich einer einstündigen ASV-Anwendung (PaceWave™, ResMed). Der pCO2- (PtcCO2) und SaO2-Wert wurden transkutan gemessen; der Wachzustand wurde mittels EEG erfasst. Auswertungen erfolgten 30 min vor und nach der ASV sowie während der einstündigen ASV. Ergebnisse: 20 HI-Patienten (19 männlich; Alter 79 ± 12 Jahre) und 15 gesunde Probanden (13 männliche; Alter 25 ± 4 Jahre) wurden eingeschlossen. Im Wachzustand war die ASV mit einem Trend zu niedrigeren PtcCO2- und höheren SaO2-Werten im Vergleich zu Baseline assoziiert, sowohl bei den HI-Patienten (von 34,4 ± 3,2 auf 33,7 ± 3,8 mm Hg bzw. von 93,8 ± 2,6 auf 94,9 ± 2,6%) als auch bei den gesunden Probanden (von 39,5 ± 3,0 auf 38,2 ± 3,8 mmHg bzw. von 96,9 ± 1,3 auf 97,8 ± 0,9%). Im Schlaf stieg während der ASV bei den HI-Patienten der PtcCO2-Wert auf 36,3 ± 3,8 mmHg, und der SaO2-Wert ging auf 93,8 ± 2,6% zurück; ähnlich verhielt es sich bei den gesunden Probanden (PtcCO2 41,7 ± 3,0 mmHg; SaO2 97,1 ± 1,2). Alle Vergleiche waren statistisch signifikant (p ≤ 0,05, mit Ausnahme der PtcCO2-Reduktion bei beiden Gruppen im Wachzustand). Schlussfolgerungen: Die ASV-Therapie könnte im Wachzustand zu Hyperventilation führen, im Schlaf jedoch stieg der PtcCO2-Wert in den mittleren Normbereich, was bei HI-Patienten mit CSR erstrebenswert wäre.Übersetzung aus Respiration 2015;89:374-382 (DOI:10.1159/000375312)
Kidney Dysfunction Increases Mortality and Incident Events after Young Stroke: The FUTURE Study
Authors: Synhaeve Nathalie E. , van Alebeek Mayte E. , Arntz Renate M. , Maaijwee Noortje A.M. , Rutten-Jacobs Loes C.A. , Schoonderwaldt Henny C. , de Kort Paul L.M. , van der Vlugt Maureen J. , Van Dijk Ewoud J. , Wetzels Jack F.M. , de Leeuw Frank-Erik
Published: May 2016

Background: In about 30% of young stroke patients, no cause can be identified. In elderly patients, kidney dysfunction has been suggested as a contributing risk factor for mortality as well as stroke. There are hypotheses that novel non-traditional risk factors, like chronic inflammation and oxidative stress, are involved in chronic kidney disease, affecting the cerebral microvasculature that would in turn lead to stroke. Our objective is to investigate the influence of kidney dysfunction on long-term mortality and incident vascular events after stroke in young adults aged 18 through 50 and if this relationship would be independent of other cardiovascular risk factors. Methods: We prospectively included 460 young stroke patients with an ischemic stroke or transient ischemic attack admitted to our department between January 1, 1980 and November 1, 2010. Follow-up was done between 2014 and 2015. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine levels and was divided in 3 subgroups: eGFR <60, 60-120 and >120 ml/min/1.73 m2. Cox proportional hazard models were used to determine the effect of kidney dysfunction on mortality and incident vascular events, adjusting for cardiovascular risk factors. Results: An eGFR <60 (HR 4.6; 95% CI 2.6-8.2) was associated with an increased risk of death and an increased risk of incident stroke (HR 4.1; 95% CI 1.9-9.0) independent of cardiovascular risk factors, but it was not associated with other vascular events. The point estimate for the 15-year cumulative mortality was 70% (95% CI 46-94) for patients with a low eGFR, 24% (95% CI 18-30) for patients with a normal eGFR and 30% (95% CI 12-48) for patients with a high eGFR. The point estimate for the 15-year cumulative risk of incident stroke was 45% (95% CI 16-74) for patients with a low eGFR, 13% (95% CI 9-17) for patients with a normal eGFR and 8% (95% CI 0-18) for patients with a high eGFR. Conclusions: Kidney dysfunction is related to long-term mortality and stroke recurrence, but not to incident cardiovascular disease, on average 11 years after young stroke. This warrants a more intensive follow-up of young stroke patients with signs of kidney dysfunction in the early phase. In addition, the clear association between kidney dysfunction and incident stroke seen in our young stroke population might be a first step in the recognition of kidney dysfunction as a new risk factor for the development of stroke at young age. Also, it can lead to new insights in the etiological differences between cardiovascular and cerebrovascular disease.
Natakalim Ameliorates Isoproterenol-Induced Chronic Heart Failure by Protecting against Endothelial Dysfunction
Authors: Zhong Mingli , Zhou Hongmin , Long Chaoliang , Zhang Yanfang , Cui Wenyu , Zhang Hao , Wang Hai
Published: May 2016

The pharmacological effects and underlying mechanisms of natakalim, a novel SUR2B/Kir6.1-KATP channel opener, against chronic heart failure induced by isoproterenol in rats were investigated. Male Wistar rats were administered isoproterenol subcutaneously (85 mg/kg, 7 days) to induce chronic heart failure and were then treated with natakalim or saline for 6 weeks. Their blood pressure, heart rates and cardiac functions were measured using an 8-channel physiological recorder. Sophisticated technologies such as histological analysis, ELISA, radioimmunoassay, immunohistochemistry, real-time PCR and western blotting were employed for analysis. Natakalim (1, 3, 9 mg/kg/day, orally) or saline was administered for 6 weeks orally via a gastric tube to rats that had been injected with isoproterenol. Natakalim remarkably inhibited changes in left ventricular hemodynamic parameters and decreased the heart mass index, the left ventricular weight index, right ventricular weight index and lung weight index. Histological examination demonstrated no significant hypertrophy or fibrosis in the hearts of the natakalim-treated rats. Mechanistically, natakalim attenuates the elevation of plasma nitric oxide (NO) level and inducible NO synthase in cardiac tissue induced by isoproterenol. Additionally, natakalim inhibits the endothelin signaling system by decreasing both the content of endothelin-1 in the plasma and the protein levels of cardiac endothelin receptors A and B. Moreover, natakalim could augment the plasma prostacyclin concentration. In conclusion, our study provides evidence that natakalim effectively ameliorates isoproterenol-induced chronic heart failure in rats by protecting against endothelial dysfunction.
Di-Calcium Phosphate and Phytosphingosine as an Innovative Acid-Resistant Treatment to Occlude Dentine Tubules
Authors: Sauro Salvatore , Lin Ching-Yang , Bikker Floris J. , Cama Giuseppe , Dubruel Peter , Soria José M. , D''Onofrio Alessia , Gillam David
Published: May 2016

The present investigation evaluated the ability of an experimental di-calcium phosphate (DCP) desensitising agent used alone or combined with phytosphingosine (PHS) to occlude dentine tubules and resist a citric acid (CA) or artificial saliva (AS) challenge. Three groups of human dentine specimens (DS) were treated with the following: (1) PHS alone, (2) DCP or (3) a combination of PHS and DCP. Dentine hydraulic conductance of DS was evaluated using a digital flow sensor at 6.9 kPa. The average fluid volume for each of the treated DS was used to calculate the total dentine permeability reduction (%P) prior to and following CA immersion for 1 min or AS immersion for 4 weeks. The treated DS were subjected to both scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy analysis. Statistically significant differences (%P) were identified between the groups by ANOVA and Fisher's multiple comparison test (p < 0.05), respectively. Interestingly, both PHS and DCP appeared to work synergistically. DS treated with DCP or PHS/DCP demonstrated a significant reduction (%P) prior to and following CA or AS challenge (p < 0.05). Both the SEM and FTIR analyses showed consistent brushite crystals occluding the dentine tubules. Conversely, the application of PHS alone failed to demonstrate any significant reduction of dentine permeability (p > 0.05) or show any evidence of occlusion of the dentine tubules. DCP can be used alone or combined with PHS to decrease the dentine permeability as well as to resist a CA and AS challenge. These results would, therefore, suggest that DCP may be a suitable treatment option for dentine hypersensitivity.
Family-Based Genetic Association for Molar-Incisor Hypomineralization
Authors: Jeremias Fabiano , Pierri Ricardo A.G. , Souza Juliana F. , Fragelli Camila Maria B. , Restrepo Manuel , Finoti Livia S. , Bussaneli Diego G. , Cordeiro Rita C.L. , Secolin Rodrigo , Maurer-Morelli Claudia V. , Scarel-Caminaga Raquel M. , Santos-Pinto Lourdes
Published: May 2016

Despite some evidence of genetic and environmental factors on molar-incisor hypomineralization (MIH), its aetiology remains unclear. This family-based genetic association study aimed more comprehensively to investigate the genetic carriage potentially involved in MIH development. DNA was obtained from buccal cells of 391 individuals who were birth family members of 101 Brazilian nuclear families. Sixty-three single nucleotide polymorphisms (SNPs) were investigated in 21 candidate genes related to amelogenesis using the TaqMan™ OpenArray™ Genotyping platform. All SNPs were genotyped in 165 birth family members unaffected by MIH, 96 with unknown MIH status and 130 affected individuals (50.7% with severe MIH). Association analysis was performed by the transmission/disequilibrium test (TDT), and statistical results were corrected using the false discovery rate. Significant results were obtained for SNPs rs7821494 (FAM83H gene, OR = 3.7; 95% CI = 1.75-7.78), rs34367704 (AMBN gene, OR = 2.7; 95% CI = 1.16-6.58), rs3789334 (BMP2 gene, OR = 2.9; 95% CI = 1.34-6.35), rs6099486 (BMP7 gene, OR = 2.2; 95% CI = 1.14-4.38), rs762642 (BMP4 gene, OR = 2.3; 95% CI = 1.38-3.65), rs7664896 (ENAM gene, OR = 2.1; 95% CI = 1.19-3.51), rs1711399 (MMP20 gene, OR = 0.4; 95% CI = 0.20-0.72), rs1711423 (MMP20 gene, OR = 2.1; 95% CI = 1.18-3.61), rs2278163 (DLX3 gene, OR = 2.8; 95% CI = 1.26-6.41), rs6996321 (FGFR1 gene, OR = 2.7; 95% CI = 1.20-5.88), and rs5979395 (AMELX gene, OR = 11.7; 95% CI = 1.63-84.74). Through this family-based association study, we concluded that variations in genes related to amelogenesis were associated with the susceptibility to develop MIH. This result is in agreement with the multifactorial idea of the MIH aetiology, but further studies are necessary to investigate more thoroughly the factors that could influence MIH.
Vascular Function in Children with Low Birthweight and Its Relationship with Early Markers of Cardiovascular Risk
Authors: Joo Turoni Claudio , Chaila Zulema , Chahla Rossana , Bazán de Casella María Cristina , Peral de Bruno María
Published: May 2016

Low birthweight (LBW) increases the risk of developing cardiovascular diseases (CVD). Few studies have established its impact at early ages. Aims: To study endothelial function (EF) and arterial stiffness (AS) and their relationship to early markers of CVD risk in children with LBW. Methods: In children with LBW (4-6 years; n = 53), anthropometric, haemodynamic and laboratory parameters, including HOMA-IR, hs-CRP, adiponectin and leptin, were determined. EF and AS were evaluated by digital pulse plethysmography. Data were compared with a control group (n = 33). Results: In both groups, anthropometric parameters remained within normal limits. Insulin and HOMA-IR had normal values, but they were significantly augmented in LBW children. LBW children showed higher leptin and hs-CRP levels than the control group. The LBW group had decreased EF (37.5 ± 5.6%) compared with the control group (75.0 ± 11.9%; p < 0.01), however without differences in AS. In LBW children, EF was negatively correlated with waist circumference, leptin, hs-CRP and with a cumulative score of risk factors. Conclusions: LBW children display altered EF that is related to early changes in CVD risk factors. The differences found in the metabolic parameters might indicate a pro-inflammatory state. This hypothesis is also supported by the laboratory findings and the correlation between EF and the number of CVD risk factors, suggesting that very early lifestyle interventions may be needed.
The Impact of Body Mass Index on the Thrombolytic Treatment of Acute Ischemic Stroke
Authors: Chatzikonstantinou Anastasios , Ebert Anne D. , Wolf Marc E.
Published: May 2016

Background: Body weight and body mass index (BMI) are regularly assessed factors in stroke patients for manifold reasons. However, their potential role specifically in intravenous thrombolysis has not been thoroughly examined. Methods: Data from 865 consecutive acute ischemic stroke patients treated with intravenous thrombolysis were analyzed. Patients were divided into different BMI categories (underweight, normal weight, overweight, obese) and compared based on the following factors: time window of treatment, clinical scores National Institute of Health Stroke Scale Score (NIHSS), modified Rankin scale (mRS) on admission and discharge, risk factors, stroke characteristics and thrombolysis complications. Recombinant tissue plasminogen activator (rtPA) doses relative to body weight and blood volume were also assessed. In a separate analysis, patients weighing up to 100 and >100 kg were compared. Results: Eighteen patients (2.1%) were underweight, 336 (38.8%) overweight, 194 (22.4%) obese and 317 (36.7%) had normal weight. Higher BMI category was associated with younger age, thrombolytic treatment later than 4.5 h, arterial hypertension, diabetes and higher relative rtPA dose relative to blood volume (p < 0.001). There were no significant differences concerning NIHSS and mRS scores or thrombolysis complications. Forty-six patients (5.3%) weighed over 100 kg. They were younger (p = 0.002) and treated later than patients under 100 kg (p < 0.001). Mean rtPA dose relative to body weight and to blood volume was significantly lower (0.7 vs. 0.9 mg/kg, p < 0.001 and 13 vs. 13.9 mg/l, p < 0.001). There was a marginal difference in NIHSS score improvement ≥4 points (26.1 vs. 40.2%, p = 0.038); otherwise, no outcome differences were found. Conclusion: BMI category does not significantly influence clinical outcome after thrombolysis. However, relevant NIHSS improvement was found more often in patients weighing up to 100 kg compared to those over 100 kg. Interestingly, patients with higher BMI or weight >100 kg were thrombolysed later than other patients.
Coexistence of Mosaic Uniparental Isodisomy and a KCNJ11 Mutation Presenting as Diffuse Congenital Hyperinsulinism and Hemihypertrophy
Authors: Kocaay Pınar , Şiklar Zeynep , Ellard Sian , Yagmurlu Aydın , Çamtosun Emine , Erden Esra , Berberoglu Merih , Flanagan Sarah E.
Published: May 2016

Background: Isolated hyperinsulinaemic hypoglycaemia (HH) commonly results from recessively inherited mutations in the ABCC8 and KCNJ11 genes that are located on chromosome 11p15.1. More rarely, HH can feature in patients with Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder, resulting from defects at a differentially methylated region telomeric to the K-ATP channel genes at chromosome 11p15.5. Subject: We undertook genetic testing in a patient with diazoxide-unresponsive HH diagnosed at birth. Physical examination later revealed hemihypertrophy of the right arm, a feature of BWS. Results: We identified a novel mosaic, paternally-inherited KCNJ11 mutation(s) in the patient. Further analysis confirmed uniparental disomy (UPD) of chromosome 11, which extended across the KCNJ11 gene at 11p15.1 and the BWS locus at 11p15.5. Conclusion: These results highlight the importance of considering UPD as a mechanism of disease in patients with HH and a paternally inherited K-ATP channel mutation, especially when additional syndromic features are present.
Hepatic lipase inactivation decreases atherosclerosis in insulin resistance by reducing LIGHT/Lymphotoxin β-Receptor pathway
Authors: Andrés-Blasco Irene , Vinué Àngela , Herrero-Cervera Andrea , Martínez-Hervás Sergio , Nuñez Laura , Piqueras Laura , Ascaso Juan F. , Sanz MarÍa Jesús , Burks Deborah Jane , González-Navarro Herminia
Published: May 2016

Coexistence of insulin resistance (IR) and metabolic syndrome (MetS) increases the risk of cardiovascular disease (CVD). Genetic studies in diabetes have linked Hepatic Lipase (HL) to an enhanced risk of CVD while others indicate a role of HL in inflammatory cells. Thus, we explored the role of HL on atherosclerosis and inflammation in a mouse model of MetS/IR, (apoE-/-Irs2+/- mice) and in patients with MetS and IR. HL-deficiency in apoE-/-Irs2+/- mice reduced atheroma size, plaque vulnerability, leukocyte infiltration and macrophage proliferation. Compared with apoE-/-Irs2+/-HL+/+ mice, MCP1, TNFa and IL6 plasma levels, pro-inflammatory Ly6Chi monocytes and activated(CD69+)-T lymphocytes were also decreased in apoE-/-Irs2+/-HL-/- mice. The LIGHT (Tumour necrosis factor ligand superfamily member 14, TNFSF14)/ Lymphotoxin β-Receptor(LTβ-R) pathway, which is involved in T-cell and macrophage activation, was diminished in plasma and in apoE-/-Irs2+/-HL-/- mouse atheromas. Treatment of apoE-/-Irs2+/-HL-/- mice with LIGHT increased the number of Ly6Chi-monocytes and lesion size. Acutely LIGHT-treated apoE-/- mice displayed enhanced proliferating Ly6Chi-monocytes and increased activation of the mitogen-activated protein kinase p38, suggesting that LIGHT/LTβ-R axis might promote atherogenesis by increasing proinflammatory monocytes and proliferation. Notably, MetS-IR subjects with increased atherosclerosis displayed up-regulation of the LIGHT/LTβ-R axis, enhanced inflammatory monocytes and augmented HL mRNA expression in circulating leukocytes. Thus, HL-deficiency decreases atherosclerosis in MetS/IR states by reducing inflammation and macrophage proliferation which are partly attributed to reduced LIGHT/LTβ-R pathway. These studies identify the LIGHT/LTβ-R axis as a main pathway in atherosclerosis and suggest that its inactivation might ameliorate inflammation and macrophage proliferation associated with atherosclerosis burden in MetS/IR.

Supplementary Material to this article is available at www.thrombosis-online.com.
c-Myb Regulates Proliferation and Differentiation of Adventitial Sca1
+
Vascular Smooth Muscle Cell Progenitors by Transactivation of Myocardin
Authors: Shikatani Eric A. , Chandy Mark , Besla Rickvinder , Li Cedric C. , Momen Abdul , El-Mounayri Omar , Robbins Clinton S. , Husain Mansoor
Published: May 2016

Objective—

Vascular smooth muscle cells (VSMCs) are believed to dedifferentiate and proliferate in response to vessel injury. Recently, adventitial progenitor cells were implicated as a source of VSMCs involved in vessel remodeling. c-Myb is a transcription factor known to regulate VSMC proliferation in vivo and differentiation of VSMCs from mouse embryonic stem cell–derived progenitors in vitro. However, the role of c-Myb in regulating specific adult vascular progenitor cell populations was not known. Our objective was to examine the role of c-Myb in the proliferation and differentiation of Sca1
+
adventitial VSMC progenitor cells.

Approach and Results—

Using mice with wild-type or hypomorphic
c-myb
(
c-myb

h/h

), BrdU (bromodeoxyuridine) uptake and flow cytometry revealed defective proliferation of Sca1
+
adventitial VSMC progenitor cells at 8, 14, and 28 days post carotid artery denudation injury in
c-myb

h/h

arteries.
c-myb

h/h

cKit
+
CD34
−
Flk1
−
Sca1
+
CD45
−
Lin
−
cells failed to proliferate, suggesting that
c-myb
regulates the activation of specific Sca1
+
progenitor cells in vivo and in vitro. Although expression levels of transforming growth factor-β1 did not vary between wild-type and
c-myb

h/h

carotid arteries, in vitro differentiation of
c-myb

h/h

Sca1
+
cells manifested defective transforming growth factor-β1–induced VSMC differentiation. This is mediated by reduced transcriptional activation of myocardin because chromatin immunoprecipitation revealed c-Myb binding to the myocardin promoter only during differentiation of Sca1
+
cells, myocardin promoter mutagenesis identified 2 specific c-Myb–responsive binding sites, and adenovirus-mediated expression of myocardin rescued the phenotype of
c-myb

h/h

progenitors.

Conclusions—

These data support a role for c-Myb in the regulation of VSMC progenitor cells and provide novel insight into how
c-myb
regulates VSMC differentiation through myocardin.