bluuebunny/crossref_metadata_2025 huggingface dataset:
A Real‐Time Lane Detection Algorithm Based on Intelligent CCD Parameters Regulation
Authors: Ge Ping-shu , Guo Lie , Xu Guo-kai , Zhang Rong-hui , Zhang Tao
Published: December 2012

Lane departure warning system (LDWS) has been regarded as an efficient method to lessen the damages of road traffic accident resulting from driver fatigue or inattention. Lane detection is one of the key techniques for LDWS. To overcome the contradiction between complexity of algorithm and the real‐time requirement for vehicle onboard system, this paper introduces a new lane detection method based on intelligent CCD parameters regulation. In order to improve the real‐time capability of the system, a CCD parameters regulating method is proposed which enhances the contrast between lane line and road surfaces and reduces image noise, so it lays a good foundation for the following lane detection. Hough transform algorithm is improved by selection and classification of seed points. Finally the lane line is extracted through some restrictions. Experimental results verify the effectiveness of the proposed method, which improves not only real‐time capability but also the accuracy of the system.
A Fuzzy Approach to Robust Control of Stochastic Nonaffine Nonlinear Systems
Authors: Gang Ting-Ting , Yang Jun , Gao Qing , Zhao Yu , Qiu Jianbin
Published: December 2012

This paper investigates the stabilization problem for a class of discrete‐time stochastic non‐affine nonlinear systems based on T‐S fuzzy models. Based on the function approximation capability of a class of stochastic T‐S fuzzy models, it is shown that the stabilization problem of a stochastic non‐affine nonlinear system can be solved as a robust stabilization problem of the stochastic T‐S fuzzy system with the approximation errors as the uncertainty term. By using a class of piecewise dynamic feedback fuzzy controllers and piecewise quadratic Lyapunov functions, robust semiglobal stabilization condition of the stochastic non‐affine nonlinear systems is formulated in terms of linear matrix inequalities. A simulation example illustrating the effectiveness of the proposed approach is provided in the end.
Dynamic Behaviors of a Nonautonomous Discrete Predator‐Prey System Incorporating a Prey Refuge and Holling Type II Functional Response
Authors: Wu Yumin , Chen Fengde , Chen Wanlin , Lin Yuhua
Published: December 2012

A nonautonomous discrete predator‐prey system incorporating a prey refuge and Holling type II functional response is studied in this paper. A set of sufficient conditions which guarantee the persistence and global stability of the system are obtained, respectively. Our results show that if refuge is large enough then predator species will be driven to extinction due to the lack of enough food. Two examples together with their numerical simulations show the feasibility of the main results.
A 3D Visualization Method for Bladder Filling Examination Based on EIT
Authors: He Wei , Ran Peng , Xu Zheng , Li Bing , Li Song-nong
Published: December 2012

As the researches of electric impedance tomography (EIT) applications in medical examinations deepen, we attempt to produce the visualization of 3D images of human bladder. In this paper, a planar electrode array system will be introduced as the measuring platform and a series of feasible methods are proposed to evaluate the simulated volume of bladder to avoid overfilling. The combined regularization algorithm enhances the spatial resolution and presents distinguishable sketch of disturbances from the background, which provides us with reliable data from inverse problem to carry on to the three-dimensional reconstruction. By detecting the edge elements and tracking down the lost information, we extract quantitative morphological features of the object from the noises and background. Preliminary measurements were conducted and the results showed that the proposed algorithm overcomes the defects of holes, protrusions, and debris in reconstruction. In addition, the targets' location in space and roughly volume could be calculated according to the grid of finite element of the model, and this feature was never achievable for the previous 2D imaging.
Prescribing Optimal Nutrition and Physical Activity as “First-Line” Interventions for Best Practice Management of Chronic Low-Grade Inflammation Associated with Osteoarthritis: Evidence Synthesis
Authors: Dean Elizabeth , Gormsen Hansen Rasmus
Published: December 2012

Low-grade inflammation and oxidative stress underlie chronic osteoarthritis. Although best-practice guidelines for osteoarthritis emphasize self-management including weight control and exercise, the role of lifestyle behavior change to address chronic low-grade inflammation has not been a focus of first-line management. This paper synthesizes the literature that supports the idea in which the Western diet and inactivity are proinflammatory, whereas a plant-based diet and activity are anti-inflammatory, and that low-grade inflammation and oxidative stress underlying osteoarthritis often coexist with lifestyle-related risk factors and conditions. We provide evidence-informed recommendations on how lifestyle behavior change can be integrated into “first-line” osteoarthritis management through teamwork and targeted evidence-based interventions. Healthy living can be exploited to reduce inflammation, oxidative stress, and related pain and disability and improve patients’ overall health. This approach aligns with evidence-based best practice and holds the promise of eliminating or reducing chronic low-grade inflammation, attenuating disease progression, reducing weight, maximizing health by minimizing a patient’s risk or manifestations of other lifestyle-related conditions hallmarked by chronic low-grade inflammation, and reducing the need for medications and surgery. This approach provides an informed cost effective basis for prevention, potential reversal, and management of signs and symptoms of chronic osteoarthritis and has implications for research paradigms in osteoarthritis.
Identification and Functional Annotation of Genome-Wide ER-Regulated Genes in Breast Cancer Based on ChIP-Seq Data
Authors: Ding Min , Wang Haiyun , Chen Jiajia , Shen Bairong , Xu Zhonghua
Published: December 2012

Estrogen receptor (ER) is a crucial molecule symbol of breast cancer. Molecular interactions between ER complexes and DNA regulate the expression of genes responsible for cancer cell phenotypes. However, the positions and mechanisms of the ER binding with downstream gene targets are far from being fully understood. ChIP-Seq is an important assay for the genome-wide study of protein-DNA interactions. In this paper, we explored the genome-wide chromatin localization of ER-DNA binding regions by analyzing ChIP-Seq data from MCF-7 breast cancer cell line. By integrating three peak detection algorithms and two datasets, we localized 933 ER binding sites, 92% among which were located far away from promoters, suggesting long-range control by ER. Moreover, 489 genes in the vicinity of ER binding sites were identified as estrogen response elements by comparison with expression data. In addition, 836 single nucleotide polymorphisms (SNPs) in or near 157 ER-regulated genes were found in the vicinity of ER binding sites. Furthermore, we annotated the function of the nearest-neighbor genes of these binding sites using Gene Ontology (GO), KEGG, and GeneGo pathway databases. The results revealed novel ER-regulated genes pathways for further experimental validation. ER was found to affect every developed stage of breast cancer by regulating genes related to the development, progression, and metastasis. This study provides a deeper understanding of the regulatory mechanisms of ER and its associated genes.
Combining Slicing and Constraint Solving for Better Debugging: The CONBAS Approach
Authors: Hofer Birgit , Wotawa Franz
Published: December 2012

Although slices provide a good basis for analyzing programs during debugging, they lack in their capabilities providing precise information regarding the most likely root causes of faults. Hence, a lot of work is left to the programmer during fault localization. In this paper, we present an approach that combines an advanced dynamic slicing method with constraint solving in order to reduce the number of delivered fault candidates. The approach is called Constraints Based Slicing (CONBAS). The idea behind CONBAS is to convert an execution trace of a failing test case into its constraint representation and to check if it is possible to find values for all variables in the execution trace so that there is no contradiction with the test case. For doing so, we make use of the correctness and incorrectness assumptions behind a diagnosis, the given failing test case. Beside the theoretical foundations and the algorithm, we present empirical results and discuss future research. The obtained empirical results indicate an improvement of about 28% for the single fault and 50% for the double-fault case compared to dynamic slicing approaches.
Preclinical Evaluation of Oncolytic Δγ134.5 Herpes Simplex Virus Expressing Interleukin-12 for Therapy of Breast Cancer Brain Metastases
Authors: Cody James J. , Scaturro Pietro , Cantor Alan B. , Yancey Gillespie G. , Parker Jacqueline N. , Markert James M.
Published: December 2012

The metastasis of breast cancer to the brain and central nervous system (CNS) is a problem of increasing importance. As improving treatments continue to extend patient survival, the incidence of CNS metastases from breast cancer is on the rise. New treatments are needed, as current treatments are limited by deleterious side effects and are generally palliative. We have previously described an oncolytic herpes simplex virus (HSV), designated M002, which lacks both copies of theγ134.5 neurovirulence gene and carries a murine interleukin 12 (IL-12) expression cassette, and have validated its antitumor efficacy in a variety of preclinical models of primary brain tumors. However, M002 has not been yet evaluated for use against metastatic brain tumors. Here, we demonstrate the following: both human breast cancer and murine mammary carcinoma cells support viral replication and IL-12 expression from M002; M002 replicates in and destroys breast cancer cells from a variety of histological subtypes, including “triple-negative” and HER2 overexpressing; M002 improves survival in an immunocompetent model more effectively than does a non-cytokine control virus. Thus, we conclude from this proof-of-principle study that aγ134.5-deleted IL-12 expressing oncolytic HSV may be a potential new therapy for breast cancer brain metastases.
Fatigue Reliability Assessment of Steel Member Using Probabilistic Stress-Life Method
Authors: Kang Dae-Hung , Jang Changhwan , Park Yeon-Soo , Han Suk-Yeol , Kim Jin Ho
Published: December 2012

The fatigue reliability of a steel member in a bridge is estimated by using the probabilistic stress-life method. The stress history of a member is defined as the loading block when a truck passes over a bridge, and the stress range frequency distribution of the stress history is obtained by a stress range frequency analysis. A probabilistic method is applied to the stress range frequency distribution, and the parameters of the probability distribution for the stress range frequency distribution are used in a numerical simulation. To obtain the probability of failure of a member under a loading block, Monte Carlo simulation is performed in conjunction with Miner's rule, the modified Miner's rule, and Haibach's rule for fatigue damage evaluation. Through these analyses procedures, we obtain an evaluation method for fatigue reliability that can predict the block number of the failure load and residual fatigue life.
Economic Evaluation on the MOX Fuel in the Closed Fuel Cycle
Authors: Zheng Youqi , Wu Hongchun , Cao Liangzhi , Jia Shizhuang
Published: December 2012

The mixed oxide (MOX) fuel is one of the most important fuels for the advanced reactors in the future. It is flexible to be applied either in the thermal reactor like pressurized water reactor (PWR) or in the fast reactor (FR). This paper compares the two approaches from the view of fuel cost. Two features are involved. (1) The cost of electricity (COE) is investigated based on the simulation of realistic operation of a practical PWR power plant and a typical fast breeder reactor design. (2) A new economic analysis model is established, considering the discount rate and the revenue of the reprocessed plutonium besides the traditional costs in the processes of fuel cycle. The sensitivity of COE to the changing parameters is also analyzed. The results show that, in the closed fuel cycle, the fuel cost of applying MOX fuels in the FBR is about 25% lower than that in the PWR at the current operating and fuel cycle level.
Pancolitis with Ischemic Injury as a Complication of Immunosuppressive Treatment in a Patient with Autoimmune Hepatitis: A Case Report
Authors: Dalbeni A. , Capoferro E. , Bernardoni L. , Capelli P. , Caliò A. , Gabbrielli A. , Capra F.
Published: December 2012

Ischemic colitis is a serious drug-induced adverse event. There are only few cases of immunosuppression-associated ischemic colitis described in the literature, but none with a pancolitis-like manifestation. We report the case of a 72-year-old female patient who developed a pancolitis with ischemic injury on immunosuppressive treatment with steroids and azathioprine for autoimmune hepatitis. The patient presented with massive rectal bleeding. Colonoscopy confirmed the diagnosis of pancolitis. The results of histological examination indicated drug-induced ischemic colitis involving the entire colon. This is the first case of ischemic pancolitis mimicking an inflammatory bowel disease (IBD) in a patient with immunosuppressive therapy.
Structural Optimization of Slender Robot Arm Based on Sensitivity Analysis
Authors: Luo Zhong , Zhao Xueyan , Liang Le , Wang Fei
Published: December 2012

An effective structural optimization method based on a sensitivity analysis is proposed to optimize the variable section of a slender robot arm. The structure mechanism and the operating principle of a polishing robot are introduced firstly, and its stiffness model is established. Then, a design of sensitivity analysis method and a sequential linear programming (SLP) strategy are developed. At the beginning of the optimization, the design sensitivity analysis method is applied to select the sensitive design variables which can make the optimized results more efficient and accurate. In addition, it can also be used to determine the scale of moving step which will improve the convergency during the optimization process. The design sensitivities are calculated using the finite difference method. The search for the final optimal structure is performed using the SLP method. Simulation results show that the proposed structure optimization method is effective in enhancing the stiffness of the robot arm regardless of the robot arm suffering either a constant force or variable forces.
Migration, Occupational Mobility, and Regional Escalators in Scotland
Authors: van Ham Maarten , Findlay Allan , Manley David , Feijten Peteke
Published: December 2012

This paper seeks to unpick the complex relationship between an individual’s migration behaviour, their place of residence, and their occupational performance in the Scottish labour market between 1991 and 2001. We investigate whether Edinburgh has emerged as an occupational escalator region and whether individuals moving there experience more rapid upward occupational mobility than those living and moving elsewhere. Using country of birth, we also control for an individual’s propensity to make long distance moves during earlier periods of their life course. Using data from the Scottish Longitudinal Study, linking 1991 and 2001 individual census records, and logistic regressions, we show that those who migrate over long distances within or to Scotland are most likely to achieve upward occupational mobility. We also found that Edinburgh is by far the most important regional escalator in Scotland; those moving to Edinburgh are the most likely to experience upward occupational mobility from low to high occupational status jobs. This is an important finding as most of the literature on escalator regions focuses on international mega cities.
The Value of Private Patient Information in the Physician-Patient Relationship: A Game-Theoretic Account
Authors: De Jaegher Kris
Published: December 2012

This paper presents a game-theoretical model of the physician-patient relationship. There is a conflict of interests between physician and patient, in that the physician prefers the patient to always obtain a particular treatment, even if the patient would not consider this treatment in his interest. The patient obtains imperfect cues of whether or not he needs the treatment. The effect of an increase in the quality of the patient’s private information is studied, in the form of an improvement in the quality of his cues. It is shown that when the patient’s information improves in this sense, he may either become better off or worse off. The precise circumstances under which either result is obtained are derived.
Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders
Authors: Jun Heechul , Mohammed Qasim Hussaini Syed , Rigby Michael J. , Jang Mi-Hyeon
Published: December 2012

Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.
A New Extended Jacobi Elliptic Function Expansion Method and Its Application to the Generalized Shallow Water Wave Equation
Authors: Xiao Yafeng , Xue Haili , Zhang Hongqing
Published: December 2012

With the aid of symbolic computation, a new extended Jacobi elliptic function expansion method is presented by means of a new ansatz, in which periodic solutions of nonlinear evolution equations, which can be expressed as a finite Laurent series of some 12 Jacobi elliptic functions, are very effective to uniformly construct more new exact periodic solutions in terms of Jacobi elliptic function solutions of nonlinear partial differential equations. As an application of the method, we choose the generalized shallow water wave (GSWW) equation to illustrate the method. As a result, we can successfully obtain more new solutions. Of course, more shock wave solutions or solitary wave solutions can be gotten at their limit condition.
3D Self‐Supported Nanoarchitectured Arrays Electrodes for Lithium‐Ion Batteries
Authors: Chen Xin , Du Ying , Zhang Nai Qing , Sun Ke Ning
Published: December 2012

Three‐dimensional self‐supported nanoarchitectured arrays electrodes (3DSNAEs) consisting of a direct growth of nanoarchitectured arrays on the conductive current collector, including homogeneous and heterogeneous nanoarchitectured arrays structures, have been currently studied as the most promising electrodes owing to their synergies resulting from the multistructure hybrid and integrating heterocomponents to address the requirements (high energy and power density) of superperformance lithium ion batteries (LIBs) applied in portable electronic consumer devices, electric vehicles, large‐scale electricity storage, and so on. In the paper, recent advances in the strategies for the fabrication, selection of the different current collector substrates, and structural configuration of 3DSNAEs with different cathode and anode materials are investigated in detail. The intrinsic relationship of the unique structural characters, the conductive substrates, and electrochemical kinetic properties of 3DSNAEs is minutely analyzed. Finally, the future design trends and directions of 3DSNAEs are highlighted, which may open a new avenue of developing ideal multifunctional 3DSNAEs for further advanced LIBs.
Hybrid Extragradient Iterative Algorithms for Variational Inequalities, Variational Inclusions, and Fixed‐Point Problems
Authors: Ceng Lu-Chuan , Wen Ching-Feng
Published: December 2012

We investigate the problem of finding a common solution of a general system of variational inequalities, a variational inclusion, and a fixed‐point problem of a strictly pseudocontractive mapping in a real Hilbert space. Motivated by Nadezhkina and Takahashi′s hybrid‐extragradient method, we propose and analyze new hybrid‐extragradient iterative algorithm for finding a common solution. It is proven that three sequences generated by this algorithm converge strongly to the same common solution under very mild conditions. Based on this result, we also construct an iterative algorithm for finding a common fixed point of three mappings, such that one of these mappings is nonexpansive, and the other two mappings are strictly pseudocontractive mappings.
Synthesis and Conformational Assignment of N-(E)-Stilbenyloxymethylenecarbonyl-Substituted Hydrazones of Acetone ando-(m- andp-) Chloro- (nitro-) benzaldehydes by Means of and NMR Spectroscopy
Authors: Patorski Przemysław , Wyrzykiewicz Elżbieta , Bartkowiak Grażyna
Published: December 2012

Eighteen new N-(E)-stilbenyloxyalkylcarbonyl-substituted hydrazones ofortho- (meta- andpara-) chloro- (nitro-) benzaldehydes1–18and two analogous hydrazones of acetone19-20were prepared. The stereochemical behavior of1–18in dimethyl-d6sulfoxide solution has been studied by NMR and NMR techniques, using spectral data of19and20as supporting material. The E-geometrical isomers and cis-/trans-amide conformers have been found for these hydrazones. Energy barriers of isomers are reported.
A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition
Authors: Whittaker Steven R. , Theurillat Jean-Philippe , Van Allen Eliezer , Wagle Nikhil , Hsiao Jessica , Cowley Glenn S. , Schadendorf Dirk , Root David E. , Garraway Levi A.
Published: January 2013

RAF inhibitors such as vemurafenib and dabrafenib block BRAF–mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAFV600E-mutant melanoma. However, some patients do not respond to this regimen, and nearly all progress to therapeutic resistance. We used a pooled RNA interference screen targeting more than 16,500 genes to discover loss-of-function events that could drive resistance to RAF inhibition. The highest ranking gene was NF1, which encodes neurofibromin, a tumor suppressor that inhibits RAS activity. NF1 loss mediates resistance to RAF and mitogen-activated protein kinase (MAPK) kinase kinase (MEK) inhibitors through sustained MAPK pathway activation. However, cells lacking NF1 retained sensitivity to the irreversible RAF inhibitor AZ628 and an ERK inhibitor. NF1 mutations were observed in BRAF–mutant tumor cells that are intrinsically resistant to RAF inhibition and in melanoma tumors obtained from patients exhibiting resistance to vemurafenib, thus showing the clinical potential for NF1-driven resistance to RAF/MEK-targeted therapies.

Significance: This work identifies functional loss of NF1 as a mediator of resistance to RAF inhibitors in BRAFV600E-mutant cancers. Furthermore, we nominate new therapeutic modalities to treat this mechanism of resistance. Cancer Discov; 3(3); 350–62. ©2012 AACR.

See related commentary by Gibney and Smalley, p. 260

This article is highlighted in the In This Issue feature, p. 239
Head-Shaking Aids in the Diagnosis of Acute Audiovestibular Loss due to Anterior Inferior Cerebellar Artery Infarction
Authors: Huh Young Eun , Koo Ja-Won , Lee Hyung , Kim Ji-Soo
Published: December 2012

Objective: To determine the patterns and diagnostic value of head-shaking nystagmus (HSN) in patients with acute audiovestibular loss. Method: Eighteen patients underwent evaluation of spontaneous nystagmus, gaze-evoked nystagmus, HSN, head impulse test, ocular tilt reaction, subjective visual vertical, bithermal caloric tests, and pure-tone audiogram. The findings were compared with those of 21 patients with labyrinthitis. Results: Fifteen patients (83%) exhibited HSN, and the horizontal HSN usually beat contralesionally (10/14, 71%). However, 9 (50%) patients also showed patterns of central HSN that included perverted HSN (n = 7), HSN in the opposite direction of spontaneous nystagmus (n = 4), and HSN beating towards unilateral canal paresis or abnormal head impulse testing (n = 3). Overall, central HSN, gaze-evoked nystagmus, and normal head impulse testing were specific for anterior inferior cerebellar artery (AICA) infarction. Moreover, central HSN was the only sign that indicated stroke in 1 of our patients with isolated audiovestibular syndrome. Lesion subtraction analyses revealed that damage to the flocculus was relatively frequent in patients with perverted HSN. Conclusions: In AICA infarction, HSN was common with both peripheral and central patterns. Careful evaluation of HSN may provide clues for AICA infarction in patients with acute audiovestibular loss.
Shared and Cell Type-Specific Mitochondrial Defects and Metabolic Adaptations in Primary Cells from PINK1-Deficient Mice
Authors: Akundi Ravi S. , Zhi Lianteng , Sullivan Patrick G. , Büeler Hansruedi
Published: December 2012

Background: Mutations in PTEN-induced kinase 1 (PINK1) cause early-onset recessive parkinsonism. PINK1 and Parkin regulate mitochondrial quality control. However, PINK1 ablation in Drosophila and cultured mammalian cell lines affected mitochondrial function/dynamics in opposite ways, confounding the elucidation of the role of PINK1 in these processes. Objective: We recently generated PINK1-deficient (PINK1-/-) mice and reasoned that primary cells from these mice provide a more physiological substrate to study the role of PINK1 in mammals and to investigate metabolic adaptations and neuron-specific vulnerability in PINK1 deficiency. Methods and Results: Using real-time measurement of oxygen consumption and extracellular acidification, we show that basal mitochondrial respiration is increased, while maximum respiration and spare respiratory capacity are decreased in PINK1-/- mouse embryonic fibroblasts (MEF), as is the membrane potential. In addition, a Warburg-like effect in PINK1-/- MEF promotes survival that is abrogated by inhibition of glycolysis. Expression of uncoupling protein-2 is decreased in PINK1-/- MEF and the striatum of PINK1-/- mice, possibly increasing the sensitivity to oxidative stress. Mitochondria accumulate in large foci in PINK1-/- MEF, indicative of abnormal mitochondrial dynamics and/or transport. Like in PINK1-/-Drosophila, enlarged/swollen mitochondria accumulate in three different cell types from PINK1-/- mice (MEF, primary cortical neurons and embryonic stem cells). However, mitochondrial enlargement is greatest and most prominent in primary cortical neurons that also develop cristae fragmentation and disintegration. Conclusion: Our results reveal mechanisms of PINK1-related parkinsonism, show that the function of PINK1 is conserved between Drosophila and mammals when studied in primary cells, and demonstrate that the same PINK1 mutation can affect mitochondrial morphology/degeneration in a cell type-specific manner, suggesting that tissue-/cell-specific metabolic capacity and adaptations determine phenotypes and cellular vulnerability in PINK1-/- mice and cells.
Clinical Impact of Somatic Mosaicism in Cases with Small Supernumerary Marker Chromosomes
Authors: Liehr T. , Klein E. , Mrasek K. , Kosyakova N. , Guilherme R.S. , Aust N. , Venner C. , Weise A. , Hamid A.B.
Published: December 2012

Somatic mosaicism is present in slightly more than 50% of small supernumerary marker chromosome (sSMC) carriers. Interestingly, non-acrocentric derived sSMC show mosaicism much more frequently than acrocentric ones. sSMC can be present in different mosaic rates, which may go below 5% of the studied cells. Also cryptic mosaicism can be present and mosaics may be differently expressed in different tissues of the body. Even though in the overwhelming majority of the cases somatic sSMC mosaicism has no direct clinical effect, there are also cases with altered clinical outcomes due to mosaicism. Also clinically important is the fact that a de novo sSMC, even present in mosaic, may be a hint of uniparental disomy (UPD). As it is under discussion to possibly replace standard karyotyping by methods like array-CGH, the impracticality of the latter to detect low-level sSMC mosaics and/or UPD has to be considered as well. Overall, sSMC mosaicism has to be studied carefully in each individual case, as it can be extremely informative and of importance, especially for prenatal genetic counseling.
Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Experimental Aortic Aneurysm Initiation and Progression
Authors: Iida Yasunori , Xu Baohui , Xuan Haojun , Glover Keith J. , Tanaka Hiroki , Hu Xiaolei , Fujimura Naoki , Wang Wei , Schultz Joshua R. , Turner Court R. , Dalman Ronald L.
Published: January 2013

Objective—

Macrophages are critical contributors to abdominal aortic aneurysm (AAA) disease. We examined the ability of MKEY, a peptide inhibitor of CXCL4–CCL5 interaction, to influence AAA progression in murine models.

Approach and Results—

AAAs were created in 10-week-old male C57BL/6J mice by transient infrarenal aortic porcine pancreatic elastase infusion. Mice were treated with MKEY via intravenous injection either (1) before porcine pancreatic elastase infusion or (2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited migration of adaptively transferred leukocytes into aneurysmal aortae in recipient mice. Although all vehicle-pretreated mice developed AAAs, aneurysms formed in only 60% (3/5) and 14% (1/7) of mice pretreated with MKEY at 10 and 20 mg/kg, respectively. MKEY pretreatment reduced aortic diameter enlargement, preserved medial elastin fibers and smooth muscle cells, and attenuated mural macrophage infiltration, angiogenesis, and aortic metalloproteinase 2 and 9 expression after porcine pancreatic elastase infusion. MKEY initiated after porcine pancreatic elastase infusion also stabilized or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation after angiotensin II infusion in apolipoprotein E–deficient mice.

Conclusion—

MKEY suppresses AAA formation and progression in 2 complementary experimental models. Peptide inhibition of CXCL4–CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.
Subsequent Development of Fibroatheromas With Inflamed Fibrous Caps Can Be Predicted by Intracoronary Near Infrared Spectroscopy
Authors: Patel Dhavalkumar , Hamamdzic Damir , Llano Raul , Patel Daivesh , Cheng Lan , Fenning Robert S. , Bannan Khalid , Wilensky Robert L.
Published: January 2013

Objective—

To prospectively evaluate whether the development of fibroatheromas exhibiting features of potential instability can be detected and predicted by serial invasive imaging.

Methods and Results—

Multivessel intravascular ultrasound and near infrared spectroscopy (NIRS) were performed in diabetic/hypercholesterolemic pigs 3, 6, and 9 months after induction. Animals were euthanized at 9 months and histological/immunohistochemical evaluation of the arteries was performed (n=304 arterial segments). Intravascular ultrasound demonstrated, over time, a progressive increase in plaque + media and necrotic core areas and positive vascular remodeling. By histology, NIRS+ lesions were significantly more likely to be a high-risk fibroatheroma (
P
=0.0001) containing larger plaque (
P
<0.0001) and necrotic core areas (
P
<0.0019) and thinner fibrous caps (
P
=0.04). NIRS + fibroatheromas possessed a greater concentration of inflammatory cells demonstrating protease activity (
P
=0.006), and proliferating (
P
=0.016), and apoptotic cells (
P
=0.04) within the fibrous cap. Eighty-eight percent of NIRS+ lesions at 3 and 6 months subsequently developed into a fibroatheroma at 9 months (
P
<0.01). By multivariate analysis NIRS positivity at 6 months predicted the subsequent presence of a fibroatheroma at 9 months (
P
=0.005; odds ratio, 2.71).

Conclusion—

The future development of inflamed fibroatheromas with thinner fibrous caps, greater plaque, and necrotic core areas, and posessing characteristics of increased plaque instability were detected by intravascular ultrasound/NIRS imaging.
Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias With Bucindolol in Patients With Chronic Heart Failure
Authors: Aleong Ryan G. , Sauer William H. , Robertson Alastair D. , Liggett Stephen B. , Bristow Michael R.
Published: December 2012

Background—

β-blockers prevent cardiac arrhythmias in patients with chronic heart failure and reduced left ventricular ejection fraction, including ventricular tachycardia/ventricular fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β-blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors.

Methods and Results—

From a substudy of the β-Blocker Evaluation of Survival Trial (n=1040), we identified those with the high functioning 389Arg versus the lower function 389Gly β
1
adrenergic receptor variant, and the loss of function α
2c
322-325 adrenergic receptor deletion versus the 322 to 325 wild-type (Wt)/deletion variant. VT/VF was recorded on case report forms as an adverse event. There were 493 Arg 389 β
1
receptor homozygotes (β
1
389 Arg/Arg) versus 547 Gly389 carriers and 207 α
2c
322-325 deletion carriers versus 833 homozygous Wts (α
2c
322-325 Wt/Wt). In all genotypes bucindolol was associated with a lower incidence of VT/VF (subhazard ratio, 0.42 [0.27–0.64];
P
=0.00006). Bucindolol reduced VT/VF in β
1
389 Arg homozygotes (subhazard ratio, 0.26 [0.14–0.50];
P
=0.00005) but not in β
1
389 Gly carriers (subhazard ratio, 0.60 [0.34–1.07];
P
=0.09). For genotype combinations, the α
2c
322-325 polymorphism altered the VT/VF bucindolol response in β1389 Gly carriers, with α
2c
deletion genotypes associated with complete efficacy loss. A test of interaction was statistically significant (
P
=0.028) for the treatment group and a β
1
389/α
2c
322-325 three genotype construct, effectively identifying patients who exhibited enhanced response, no substantial response modification and loss of response.

Conclusions—

Bucindolol prevents VT/VF in subjects with heart failure and reduced left ventricular ejection fractions, and this effect is modulated by β
1
389 Arg/Gly and α
2c
322-325 Wt/deletion adrenergic receptor polymorphisms.
Novel Insights Into the Critical Role of Bradykinin and the Kinin B2 Receptor for Vascular Recruitment of Circulating Endothelial Repair–Promoting Mononuclear Cell Subsets
Authors: Kränkel Nicolle , Kuschnerus Kira , Müller Maja , Speer Timo , Mocharla Pavani , Madeddu Paolo , Bader Michael , Lüscher Thomas F. , Landmesser Ulf
Published: December 2012

Background—

Endothelial injury is considered critical for progression of atherosclerosis and its complications in coronary artery disease (CAD). The endothelial-supportive effects of bradykinin have mainly been attributed to activation of the resident endothelium. Here we newly investigate the role of bradykinin and its B2 receptor for the recruitment and functional activation of circulating mononuclear cell subsets with endothelial-repair promoting capacity, such as CD34
+
CXCR4
+
cells, at sites of arterial injury.

Methods and Results—

Bradykinin-B2-receptor (B2R) blockade by icatibant substantially impaired recruitment of circulating CD34
+
CXCR4
+
mononuclear cells (expressing high levels of B2R) to endothelial cells in vitro and to injured arterial wall in vivo, whereas recruitment of CD14
hi
monocytes (expressing low levels of B2R) was unchanged. Moreover, the capacity of genetically
B2R
-deficient bone marrow cells to promote endothelial repair in vivo was markedly impaired as compared with wild-type bone marrow cells. B2R expression was reduced on CD34
+
CXCR4
+
mononuclear cells and endothelial repair–promoting early outgrowth cells, but not on CD14
hi
monocytes, from CAD patients as compared with healthy subjects. B2R stimulation induced CD18 activation in early outgrowth cells of healthy subjects, but not in early outgrowth cells of CAD patients. Adenoviral B2R overexpression enhanced in vivo vascular recruitment and rescued impaired endothelial repair capacity of early outgrowth cells from CAD patients.

Conclusions—

We newly report that bradykinin/B2R signaling may promote endothelial repair after arterial injury by selective recruitment and functional activation of B2R-expressing circulating mononuclear cell subsets. In CAD patients, B2R downregulation on endothelial repair–promoting circulating mononuclear cells substantially impairs the bradykinin-dependent endothelial repair, representing a novel mechanism promoting endothelial injury in CAD patients.
Statin Therapy and Outcome After Ischemic Stroke
Authors: Ní Chróinín Danielle , Asplund Kjell , Åsberg Signild , Callaly Elizabeth , Cuadrado-Godia Elisa , Díez-Tejedor Exuperio , Di Napoli Mario , Engelter Stefan T. , Furie Karen L. , Giannopoulos Sotirios , Gotto Antonio M. , Hannon Niamh , Jonsson Fredrik , Kapral Moira K. , Martí-Fàbregas Joan , Martínez-Sánchez Patricia , Milionis Haralampos J. , Montaner Joan , Muscari Antonio , Pikija Slaven , Probstfield Jeffrey , Rost Natalia S. , Thrift Amanda G. , Vemmos Konstantinos , Kelly Peter J.
Published: January 2013

Background and Purpose—

Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke.

Methods—

The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (≤72 hours after stroke), and (2) thrombolysis-treated patients.

Results—

The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29–1.56;
P
<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9–1.4;
P
=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62–0.82;
P
<0.001) and 1 year (OR, 0.80; 95% CI, 0.67–0.95;
P
=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0–2.24;
P
=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (
P
=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02–1.52;
P
=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90–1.44; 4012 patients).

Conclusion—

In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.
One-Year Progression of Moderate Asymptomatic Carotid Stenosis Predicts the Risk of Vascular Events
Authors: Balestrini Simona , Lupidi Francesca , Balucani Clotilde , Altamura Claudia , Vernieri Fabrizio , Provinciali Leandro , Silvestrini Mauro
Published: January 2013

Background and Purpose—

This study aimed at evaluating whether ultrasound monitoring of moderate asymptomatic carotid stenosis may help in identifying subjects at high risk for vascular events.

Methods—

We included 523 subjects with unilateral asymptomatic carotid stenosis of 50% to 69%. Follow-up carotid ultrasound was performed within 12 months from inclusion to detect the frequency and degree of stenosis progression. Subjects were prospectively evaluated for a median period of 42 months (interquartile range, 38–45) after a second ultrasound evaluation. Outcome measures were any stroke and transient ischemic attack, myocardial infarction, and death.

Results—

Carotid stenosis progression was associated with the occurrence of vascular events (hazard ratio, 21.57; 95% confidence interval, 11.81–39.39;
P
<0.001). During follow-up, 96.7% of subjects without progressive carotid stenosis remained free from vascular events. Among patients with progressive stenosis, 53.7% experienced a vascular event and 27.1% experienced an ipsilateral stroke.

Conclusions—

One-year moderate asymptomatic carotid stenosis progression is related to higher risk of vascular events, including ipsilateral stroke.
Vitamin K Antagonists–Associated Cerebral Hemorrhages
Authors: Dequatre-Ponchelle Nelly , Hénon Hilde , Pasquini Marta , Rutgers Matthieu P. , Bordet Régis , Leys Didier , Cordonnier Charlotte
Published: January 2013

Background and Purpose—

The high prevalence of atrial fibrillation in aging populations leads to an increasing incidence of vitamin K antagonists-associated intracerebral hemorrhages (VKAs-ICH). It remains unclear whether VKAs are causes or risk factors for ICH. We aimed at identifying the specificities of VKAs-ICH.

Methods—

We compared baseline characteristics of 545 consecutive patients receiving or not receiving VKAs before admission for spontaneous ICH. To determine whether the influence of VKAs depends on the underlying vasculopathy, that is, cerebral amyloid angiopathy in lobar, and deep perforating arteries vasculopathy in deep ICH, we compared characteristics of ICH (including volume) according to the anatomic distribution of ICH in multiple linear regression.

Results—

VKAs-ICH accounted for 83 patients, that is, 15% (95% confidence intervals, 12–18) of ICH in our cohort. The use of VKAs did not influence anatomic distribution of ICH. The impact of VKAs on ICH volume differed according to ICH location: in nonlobar ICH, VKAs use was associated with significant larger ICH volumes (median volume 25 mL vs 12 mL;
P
=0.002). In lobar ICH, VKAs use did not influence the volume (median 26 mL vs 30 mL;
P
=0.507).

Conclusions—

A similar anatomic distribution of ICH in patients with or without VKAs suggests that VKAs should not be considered as a cause of ICH because both locations are usually due to different vasculopathies (deep perforating arteries vasculopathy in deep and cerebral amyloid angiopathy in lobar). The different impact of VKAs on ICH volumes according to location suggests a different susceptibility of these vasculopathies to VKAs. This finding may lead to specific therapeutic strategies.
Contributions of Individual Atmospheric Diabatic Heating Processes to the Generation of Available Potential Energy
Authors: Romanski Joy , Rossow William B.
Published: January 2013

The generation of zonal and eddy available potential energy (Gz and Ge) as formulated by Lorenz are computed on a global-, daily-, and synoptic-scale basis to consider the contribution of each diabatic heating component separately and in combination. Using global, mostly satellite-derived datasets for the diabatic heating components and the temperature enables us to obtain Gz and, especially, Ge from observations for the first time and at higher temporal and spatial resolution than previously possible. The role of clouds in maintaining G is investigated.

The global annual mean Gz is 1.52 W m−2. Values reach a minimum of 0.63 W m−2 in the Northern Hemisphere during spring and a maximum of 2.27 W m−2 in the Southern Hemisphere during winter. The largest contributors to Gz are latent heating in the tropical upper troposphere, associated with the intertropical convergence zone in the summer hemisphere and surface sensible heat fluxes in the winter pole. Diabatic cooling by radiative fluxes (mostly longwave) generally destroys Gz.

The value of Ge is negative and is about an order of magnitude smaller than Gz, with a global annual mean of −0.29 W m−2. However, the small value of Ge results from the cancellation of the contributions from the individual diabatic heating terms, which are actually roughly similar in magnitude to their Gz contributions.

The results presented herein suggest that the large-scale dynamics of the atmosphere organize the spatial and temporal distribution of clouds and precipitation in such a way as to increase the energy available to drive the circulation, a kind of positive feedback.
The Wounded Grace: Memory, Body and Salvation in Endō Shūsaku and Rowan Williams
Authors: Kim JinHyok
Published: January 2013

Endō Shūsaku and Rowan Williams offer us crucial insights into the meaning of being truly human by paying special attention to the vulnerability and fallibility of human existence. They show that everyday human experience, albeit fragmented and ambiguous, can be conceived as windows through which God’s light shines upon the dark chamber of our self-centred ego. For Endō, God’s grace is not sought apart from the chores of ordinary life, but with and through the traces engraved in the web of relationships and contingencies in this material world. Williams’ kenotic ontology of social exchange provides us with a wider theological background in which our experience of contingencies in the material world can be understood as God’s gift. Their rich reflections do indeed show us a way to live as corporeal creatures in the world of agony, ambiguity and uncertainty.
The Narrative Substructure of 1 Peter
Authors: Sargent Benjamin
Published: January 2013

New Testament authors write with a certain historical narrative of God’s dealings with Israel in mind, through which they understand and engage with their audiences. Often this narrative is an unexpressed substructure behind a piece of writing. This is the case in 1 Peter. The narrative substructure of 1 Peter is alluded to in 1 Pet 1:10-12 and in 1:19-20. This narrative, it is argued here, is one of discontinuity. Rather than seeing the Christian communities as a continuation of God’s dealings with Israel, Peter sees the communities as exclusively occupying a climax in his narrative which contrasts with the status of Israel in the past. This narrative has significant implications for an understanding of the interpretation of scripture in 1 Peter.