bluuebunny/crossref_metadata_2025 huggingface dataset:
Do predictions of visual perception aid design?
Authors: Rosenholtz Ruth , Dorai Amal , Freeman Rosalind
Published: January 2011

Understanding and exploiting the abilities of the human visual system is an important part of the design of usable user interfaces and information visualizations. Designers traditionally learn qualitative rules of thumb for how to enable quick, easy, and veridical perception of their design. More recently, work in human and computer vision has produced more quantitative models of human perception, which take as input arbitrary, complex images of a design. In this article, we ask whether models of perception aid the design process, using our tool DesignEye as a working example of a perceptual tool incorporating such models. Through a series of interactions with designers and design teams, we find that the models can help, but in somewhat unexpected ways. DesignEye was capable of facilitating A/B comparisons between designs, and judgments about the quality of a design. However, overall “goodness” values were not very useful, showed signs of interfering with a natural process of trading off perceptual vs. other design issues, and would likely interfere with acceptance of a perceptual tool by professional designers. Perhaps most surprisingly, DesignEye, by providing in essence a simple visualization of the design, seemed to facilitate communication about not only perceptual aspects of design, but also about design goals and how to achieve those goals. We discuss resulting design principles for making perceptual tools useful in general.
Object selection in gaze controlled systems
Authors: Huckauf Anke , Urbina Mario H.
Published: January 2011

Controlling computers using eye movements can provide a fast and efficient alternative to the computer mouse. However, implementing object selection in gaze-controlled systems is still a challenge. Dwell times or fixations on a certain object typically used to elicit the selection of this object show several disadvantages. We studied deviations of critical thresholds by an individual and task-specific adaptation method. This demonstrated an enormous variability of optimal dwell times. We developed an alternative approach using antisaccades for selection. For selection by antisaccades, highlighted objects are copied to one side of the object. The object is selected when fixating to the side opposed to that copy requiring to inhibit an automatic gaze shift toward new objects. Both techniques were compared in a selection task. Two experiments revealed superior performance in terms of errors for the individually adapted dwell times. Antisaccades provide an alternative approach to dwell time selection, but they did not show an improvement over dwell time. We discuss potential improvements in the antisaccade implementation with which antisaccades might become a serious alternative to dwell times for object selection in gaze-controlled systems.
Safety alternating automata on data words
Authors: Lazić Ranko
Published: January 2011

A data word is a sequence of pairs of a letter from a finite alphabet and an element from an infinite set, where the latter can only be compared for equality. Safety one-way alternating automata with one register on infinite data words are considered, their nonemptiness is shown to be ExpSpace-complete, and their inclusion decidable but not primitive recursive. The same complexity bounds are obtained for satisfiability and refinement, respectively, for the safety fragment of linear temporal logic with freeze quantification. Dropping the safety restriction, adding past temporal operators, or adding one more register, each causes undecidability.
Well-founded semantics for description logic programs in the semantic web
Authors: Eiter Thomas , Ianni Giovambattista , Lukasiewicz Thomas , Schindlauer Roman
Published: January 2011

The realization of the Semantic Web vision, in which computational logic has a prominent role, has stimulated a lot of research on combining rules and ontologies, which are formulated in different formalisms. In particular, combining logic programming with the Web Ontology Language (OWL), which is a standard based on description logics, emerged as an important issue for linking the Rules and Ontology Layers of the Semantic Web. Nonmonotonic description logic programs (dl-programs) were introduced for such a combination, in which a pair(L,P)of a description logic knowledge baseLand a set of rulesPwith negation as failure is given a model-based semantics that generalizes the answer set semantics of logic programs. In this article, we reconsider dl-programs and present a well-founded semantics for them as an analog for the other main semantics of logic programs. It generalizes the canonical definition of the well-founded semantics based on unfounded sets, and, as we show, lifts many of the well-known properties from ordinary logic programs to dl-programs. Among these properties, our semantics amounts to a partial model approximating the answer set semantics, which yields for positive and stratified dl-programs, a total model coinciding with the answer set semantics; it has polynomial data complexity provided the access to the description logic knowledge base is polynomial; under suitable restrictions, it has lower complexity and even first-order rewritability is achievable. The results add to previous evidence that dl-programs are a versatile and robust combination approach, which moreover is implementable using legacy engines.
MWeb
Authors: Analyti Anastasia , Antoniou Grigoris , Damasio Carlos Viegas
Published: January 2011

We present a principled framework for modular Web rule bases, called MWeb. According to this framework, each predicate defined in a rule base is characterized by its defining reasoning mode, scope, and exporting rule base list. Each predicate used in a rule base is characterized by its requesting reasoning mode and importing rule base list. For legal MWeb modular rule bases
S
, the MWebAS and MWebWFS semantics of each rule base
s
∈
S
with respect to
S
are defined model-theoretically. These semantics extend the answer set semantics (AS) and the well-founded semantics with explicit negation (WFSX) on ELPs, respectively, keeping all of their semantical and computational characteristics. Our framework supports: (1) local semantics and different points of view, (2) local closed-world and open-world assumptions, (3) scoped negation-as-failure, (4) restricted propagation of local inconsistencies, and (5) monotonicity of reasoning, for fully shared predicates.
Matting and compositing of transparent and refractive objects
Authors: Yeung Sai-Kit , Tang Chi-Keung , Brown Michael S. , Kang Sing Bing
Published: January 2011

This article introduces a new approach for matting and compositing transparent and refractive objects in photographs. The key to our work is an image-based matting model, termed the
Attenuation-Refraction Matte
(ARM), that encodes plausible refractive properties of a transparent object along with its observed specularities and transmissive properties. We show that an object's ARM can be extracted directly from a photograph using simple user markup. Once extracted, the ARM is used to paste the object onto a new background with a variety of effects, including compound compositing, Fresnel effect, scene depth, and even caustic shadows. User studies find our results favorable to those obtained with Photoshop as well as perceptually valid in most cases. Our approach allows photo editing of transparent and refractive objects in a manner that produces realistic effects previously only possible via 3D models or environment matting.
Subspace video stabilization
Authors: Liu Feng , Gleicher Michael , Wang Jue , Jin Hailin , Agarwala Aseem
Published: January 2011

We present a robust and efficient approach to video stabilization that achieves high-quality camera motion for a wide range of videos. In this article, we focus on the problem of transforming a set of input 2D motion trajectories so that they are both smooth and resemble visually plausible views of the imaged scene; our key insight is that we can achieve this goal by enforcing
subspace constraints
on feature trajectories while smoothing them. Our approach assembles tracked features in the video into a trajectory matrix, factors it into two low-rank matrices, and performs filtering or curve fitting in a low-dimensional linear space. In order to process long videos, we propose a moving factorization that is both efficient and streamable. Our experiments confirm that our approach can efficiently provide stabilization results comparable with prior 3D methods in cases where those methods succeed, but also provides smooth camera motions in cases where such approaches often fail, such as videos that lack parallax. The presented approach offers the first method that both achieves high-quality video stabilization and is practical enough for consumer applications.
A nonsmooth Newton solver for capturing exact Coulomb friction in fiber assemblies
Authors: Bertails-Descoubes Florence , Cadoux Florent , Daviet Gilles , Acary Vincent
Published: January 2011

We focus on the challenging problem of simulating thin elastic rods in contact, in the presence of friction. Most previous approaches in computer graphics rely on a linear complementarity formulation for handling contact in a stable way, and approximate Coulombs's friction law for making the problem tractable. In contrast, following the seminal work by Alart and Curnier in contact mechanics, we simultaneously model contact and exact Coulomb friction as a zero finding problem of a nonsmooth function. A semi-implicit time-stepping scheme is then employed to discretize the dynamics of rods constrained by frictional contact: this leads to a set of linear equations subject to an equality constraint involving a nondifferentiable function. To solve this one-step problem we introduce a simple and practical nonsmooth Newton algorithm which proves to be reasonably efficient and robust for systems that are not overconstrained. We show that our method is able to finely capture the subtle effects that occur when thin elastic rods with various geometries enter into contact, such as stick-slip instabilities in free configurations, entangling curls, resting contacts in braid-like structures, or the formation of tight knots under large constraints. Our method can be viewed as a first step towards the accurate modeling of dynamic fibrous materials.
MYC Phosphorylation, Activation, and Tumorigenic Potential in Hepatocellular Carcinoma Are Regulated by HMG-CoA Reductase
Authors: Cao Zhongwei , Fan-Minogue Hua , Bellovin David I. , Yevtodiyenko Aleksey , Arzeno Julia , Yang Qiwei , Gambhir Sanjiv Sam , Felsher Dean W.
Published: January 2011

MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors. Cancer Res; 71(6); 2286–97. ©2011 AACR.
Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin
Authors: Zucali Paolo Andrea , Giovannetti Elisa , Destro Annarita , Mencoboni Manlio , Ceresoli Giovanni Luca , Gianoncelli Letizia , Lorenzi Elena , De Vincenzo Fabio , Simonelli Matteo , Perrino Matteo , Bruzzone Andrea , Thunnissen Erik , Tunesi Gianni , Giordano Laura , Roncalli Massimo , Peters Godefridus J. , Santoro Armando
Published: January 2011

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting.

Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients.

Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome.

Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR.
AMPK and Akt Determine Apoptotic Cell Death following Perturbations of One-Carbon Metabolism by Regulating ER Stress in Acute Lymphoblastic Leukemia
Authors: Kuznetsov Jeffim N. , Leclerc Guy J. , Leclerc Gilles M. , Barredo Julio C.
Published: January 2011

AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose- and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates [methotrexate (MTX) or pemetrexed] has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types. Our data presented herein show that sustained endoplasmic reticulum (ER) stress is the predominant mechanism behind the synergistic induction of cell death by the combination of AICAr plus the inhibitor of one-carbon metabolism, MTX, in Bp- and T-ALL, as evidenced by induction of several unfolded protein response markers leading to apoptosis. We also show for the first time that AICAr in combination with MTX significantly induces Akt phosphorylation in ALL. Under these conditions, the concomitant inhibition of Akt, a cellular antagonist of AMPK, leads to further upregulation of AMPK activity and alleviates AICAr plus MTX-induced ER stress and apoptosis. Therefore, we also show that the concomitant activation of AMPK actually rescues the cells from AICAr plus MTX-induced ER stress and apoptosis. Our data suggest that the effects of AMPK activation on cell death or survival differ contextually depending on its signaling alterations with related oncogenic pathways and provide insight into the reported paradoxical proapoptotic versus prosurvival effects of AMPK activation. Mol Cancer Ther; 10(3); 437–47. ©2011 AACR.
Nanog Is Highly Expressed in Ovarian Serous Cystadenocarcinoma and Correlated with Clinical Stage and Pathological Grade
Authors: Pan Yongmiao , Jiao Jie , Zhou Caiyun , Cheng Qi , Hu Yuting , Chen Huaizeng
Published: January 2011

Objective: Nanog is overexpressed in embryonic stem cells for cell self-renewal and differentiation. We investigated whether the Nanog expression is associated with the occurrence and development of ovarian cancer. Methods: Immunohistochemistry was used to examine the expression of Nanog in 43 normal ovarian epithelia, 110 serous cystadenomas, 80 borderline serous cystadenomas, and 107 serous cystadenocarcinomas. In the meantime, their association with various clinicopathologic features was assessed. Results: The expression intensity of Nanog in normal ovarian tissue, benign, borderline, and malignant tumors showed a gradual rising trend. Among the serous cystadenocarcinomas, 42.86% were detected to be positive for stage I, 70.97% for stage II, 95.31% for stage III, and 100% for stage IV. There was a strong correlation between Nanog and clinical stage (r = 0.418, p = 0.000). Besides, there was a 55.56% positive expression of grade I, 73.68% of grade II, and 96.67% of grade III. The correlation between Nanog and differentiation grade was dramatic (r = 0.692, p = 0.000). Conclusions: Nanog was highly expressed in ovarian serous cystadenocarcinoma, and showed a positive correlation with clinical stage and grade. Nanog may play an important role in the development of dedifferentiation and progression of serous ovarian carcinoma.
Alteration of REDD1-Mediated Mammalian Target of Rapamycin Pathway and Hypoxia-Inducible Factor-1α Regulation in Human Breast Cancer
Authors: Koo Ja Seung , Jung Woohee
Published: January 2011

Objective: The purpose of this study is to investigate REDD1-(regulated in development and DNA damage response 1) mediated regulation of the mammalian target of rapamycin (mTOR) pathway in breast cancer. Methods: A tissue microarray included samples from 224 patients with breast cancer, and 30 patients with papilloma were used as a control group. An immunohistochemistry (IHC) including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epithelial growth factor receptor, cytokeratin 5/6, glucose transporter 1 (Glut-1), hypoxia-inducible factor (HIF)-1α, REDD1, AMPK (5′-adenosine-monophosphate-activated protein kinase) α1, 14-3-3σ, phosphatase and tensin homolog, phospho-Akt, phospho-mTOR, phospho-S6, and Ki-67 was conducted. The phenotypic classification of breast cancer was performed based on the results of the IHC for ER, PR and HER2: luminal A, luminal B, HER2 overexpression and triple-negative breast cancer (TNBC). Results: Glut-1 and HIF-1α were more highly expressed in TNBC, the HER2 overexpression type and papilloma than in the luminal A and B phenotypes (p = 0.000). REDD1 expression was higher in papilloma than in breast cancer (p = 0.000), but no difference was found among the 4 breast cancer phenotypes (p = 0.307). Conclusion: In the HER2 overexpression type and TNBC, tumor cell proliferation and survival in the hypoxic tumor environment could possibly be due to disinhibition of the mTOR pathway and HIF-1α stabilization by downregulation of REDD1.
Different Expressions and DNA Methylation Patterns of Lysophosphatidic Acid Receptor Genes in Mouse Tumor Cells
Authors: Okabe Kyoko , Hayashi Mai , Wakabayashi Naoko , Yamawaki Yasuna , Teranishi Miki , Fukushima Nobuyuki , Tsujiuchi Toshifumi
Published: January 2011

Objective: Lysophosphatidic acid (LPA) receptors act as several biological effectors through LPA, which is a bioactive phospholipid. Recently, aberrant expressions of LPA receptor genes due to DNA methylation have been detected in several tumor cells. In this study, we measured expression levels and DNA methylation status of LPA receptor genes in mouse tumor cells, LL/2 lung carcinoma, B16F0 melanoma, FM3A mammary carcinoma and L1210 leukemia cells, compared with normal tissues. Methods: Total RNAs were extracted and RT-PCR analysis was performed. For DNA methylation status, bisulfite sequencing analysis was carried out, comparing outcomes with other tumor cells and normal tissues. Results: The expressions of LPA1 gene were shown in LL/2, but not in B16F0, FM3A and L1210 cells. While the LPA2 gene was expressed in all 4 tumor cells, the LPA3 gene was unexpressed in them. The LPA1 and LPA3 unexpressed cells were highly methylated, although normal tissues were all unmethylated. The DNA methylation status was correlated with gene expression levels in cancer cells. Conclusion: The present results demonstrate that DNA methylation patterns of LPA receptor genes are dependent on cancer cell types, suggesting that LPA receptors may be new molecular targets for therapeutic approaches and chemoprevention.
Validation of Glomerular Basement Membrane Thickness Changes with Aging in Minimal Change Disease
Authors: Sato Shigeru , Sasaki Yoshihiro , Adachi Akiko , Ghazizadeh Mohammad
Published: January 2011

Measurement of the normal range of glomerular basement membrane (GBM) thickness by electron microscopy is required for the diagnosis of thin basement membrane disease or diabetic nephropathy; however, this measurement is influenced by aging. The aim of this study was to introduce a simple histogram plotting method for the validation of the results of the GBM thickness measurements by the accepted arithmetic mean ± SD method. We examined renal biopsy specimens obtained from 19 patients (10 males and 9 females) with minimal change disease, ranging in age from 3 to 70 years. Renal tissue samples obtained at autopsy from a male baby (3 months old) with no renal disease were also examined. For each case, GBM thicknesses at 10–15 evenly distributed points per glomerular loop were directly measured and the arithmetic mean ± SD was calculated. Subsequently, the arithmetic mean ± SD for each group of cases classified by age into 4 groups, i.e. babyhood (3 months old), childhood (3–11 years old), adulthood (12–57 years old), and old age (60–70 years old), was determined. On the other hand, a histogram of the frequency of GBM points measured against thickness was plotted to determine the distribution pattern and the range of measurements in each age group. The histogram plot showed 4 clearly divided modes for GBM thickness. Comparison of the results obtained by the 2 methods revealed a significant correlation indicating the feasibility of the histogram plotting method as a useful adjunct to validate GBM thickness measurements.
FOXP3 Expression in Duodenal Mucosa in Pediatric Patients with Celiac Disease
Authors: Brazowski Eli , Cohen Shlomi , Yaron Ayala , Filip Irina , Eisenthal Avi
Published: January 2011

Objective: It was the aim of this study to evaluate the number of 2 lymphoid subpopulations, CD8+ cells and FOXP3+, in the duodenum mucosa from pediatric celiac patients. Methods: Tissue sections prepared from paraffin-embedded biopsies of the descending duodenum of 61 celiac patients with Marsh grade 1 (M1), M2 and M3 disease and biopsies from 21 age-matched non-celiac (NC) patients were immunohistostained with anti-CD8 or FOXP3 antibodies. Results: The histological Marsh grade correlated with the mean number of FOXP3+ cells in the lamina propria (LP) mucosa (8.9 ± 1.1, 6.8 ± 2.4, 24.5 ± 2.6 and 31.1 ± 2.8 for NC, M1, M2 and M3 biopsies, respectively; p < 0.001). Using a cutoff point of 15 cells, 95% of NC and 88% of M1 biopsies had a mean of <15 FOXP3+ cells compared with 14% for M2 and 13% for M3 biopsies. The number of FOXP3+ cells in the epithelial mucosa also correlated with transglutaminase type 2 serum levels from the celiac patients. Unlike the FOXP3+ cells, CD8+ lymphocytes were present in both LP and surface epithelial mucosa and significantly different only in the LP mucosa of the M2 and M3 groups. Conclusion: The number of FOXP3+ cells is substantially increased in the mucosa of celiac patients at advanced stages. Characterization of the activity of these cells in celiac and in other inflammatory bowel diseases will enable us to understand the significance of these cells in celiac disease.
Impact of Diabetes Mellitus on Survival in Patients with End-Stage Renal Disease: A Three-Year Follow-Up
Authors: Tomaszuk-Kazberuk Anna , Bachorzewska-Gajewska Hanna , Malyszko Jolanta , Malyszko Jacek , Mysliwiec Michal , Musial Wlodzimierz J.
Published: January 2011

Background/Aims: To assess the impact of diabetes mellitus (DM) on clinical outcome in patients with end-stage renal disease (ESRD) on a 3-year follow-up. Methods: 58 ESRD patients were divided into 2 groups according to the presence of DM. We analyzed following end points: death, cardiac arrest, myocardial infarction, stroke, hospitalizations due to cardiovascular causes, revascularization, and combined end point. Results: Among diabetics, 14 (77.8%) had significant atherosclerotic changes, in the group without DM only 8 (38.1%), p = 0.01. In the group without DM, 14 (46.7%) patients reached combined end point, while in the group with DM 16 (53.3%) patients, p = 0.0013. There were no statistical differences in mortality (p = 0.423). Conclusion: Survival of hemodialyzed diabetic patients is not inferior to nondiabetics; however, morbidity is significantly higher due to adverse cardiac events.
Factor XII Osaka: Abnormal factor XII with partially defective prekallikrein cleavage activity
Authors: Arakawa Yuya , Sugahara Yuya , Matsushita Michiko , Moriguchi Yuki , Shimohiro Hisashi , Nakagawa Mayumi , Iijima Kenji
Published: January 2011

A healthy Japanese male had reduced factor XII (FXII) activity (35%) in contrast to normal antigen levels (81%). The F12 of this proband had a 9775G to C mutation in exon 10 and an 11276G to A mutation in exon 13 that resulted in two amino acid substitutions of Ala324Pro (GCG→CCG) in the proline-rich connecting region and Gly531Glu (GGG→GAG) near the active Ser544 in the catalytic domain. His father had the nucleotide 46T/T and a heterozygous 9775G/C mutation. The FXII activity (32%) and antigen level (38%) of the father were about half that of normal individuals with 46T/T, suggesting a heterozygous cross reacting material (CRM)-negative deficiency. His mother had a 46C/T and heterozygous 11276G/A mutation, and 80% FXII activity was incompatible with the corresponding antigen level (125%), suggesting a heterozygous CRM-positive deficiency. The substitution of Ala324Pro probably caused the CRM-negative mutation and the Gly531Glu caused the CRM-positive mutation. We developed three methods based on chromogenic substrates to assay the distinct functions of FXII, namely its autoactivation on a negatively charged surface, activation by kallikrein cleavage and the prekallikrein cleavage activity of FXIIa. The ratios of autoactivated FXIIa/FXII antigen (0.80–1.10) and of kallikrein-induced FXIIa/FXII antigen (0.86–1.00) in plasma from the proband were within normal ranges, whereas those of FXIIa-induced kallikrein/FXII antigen were reduced to 0.41–0.45. In conclusion, the 9775G to C and 11276G to A mutations of F12 led to a CRM-negative and -positive FXII deficiency, and the F12 with 11276A produced a dys-functional type of FXII with a partial defect (0.41–0.45) in prekallikrein cleavage activity.
Molecular basis of antithrombin deficiency
Authors: Delev Daniel , Geisen Christof , Spannagl Michael , Krause Manuela , Miesbach Wolfgang , Heller Christine , Bergmann Frauke , Schmeink Ursula , Grossmann Ralf , Lindhoff-Last Edelgard , Seifried Erhard , Oldenburg Johannes , Pavlova Anna , Luxembourg Beate
Published: January 2011

Antithrombin (AT) is the most important physiological inhibitor of coagulation proteases. It is activated by glycosaminoglycans such as heparin. Hereditary antithrombin deficiency is a rare disease that is mainly associated with venous thromboembolism. So far, more than 200 different mutations in the antithrombin gene (SERPINC1) have been described. The aim of our study was to characterise the molecular background in a large cohort of patients with AT deficiency. Mutation analysis was performed by direct sequencing of SERPINC1 in 272 AT-deficient patients. Large deletions were identified by multiplex PCR coupled with liquid chromatography or multiplex ligation-dependent probe amplification (MLPA) analysis. To predict the effect of SERPINC1 sequence variations on the pathogenesis of AT deficiency, in silico assessments, multiple sequence alignment, and molecular graphic imaging were performed. The mutation profile consisted of 59% missense, 10% non-sense, 8% splice site mutations, 15% small deletions/insertions/duplications, and 8% large deletions. Altogether 87 different mutations, including 42 novel mutations (22 missense and 20 null mutations), were identified. Of the novel missense mutations, nine are suspected to impair the conformational changes that are needed for AT activation, two to affect the central reactive loop or the heparin binding site, and six to impair the structural integrity of the molecule. Despite the heterogeneous background of AT deficiency, 10 AT variants occurred in multiple index patients. Characterisation of the SERPINC1 mutation profile in large cohorts of patients may help to further elucidate the pathogenesis of AT deficiency and to establish genotype-phenotype associations.
A clinical-laboratory algorithm incorporating optical density value to predict heparin-induced thrombocytopenia
Authors: Bensadoun Eric , Davis George , Flynn Jeremy , Lewis Daniel , Ruf Kathryn
Published: January 2011

The diagnosis of heparin-induced thrombocytopenia (HIT) is complex and involves integrating both clinical and laboratory findings. Readily available diagnostic tests such as the heparin-dependant antibody assay (HDAA) lack desired specificity when utilised alone. A diagnostic algorithm incorporating the 4T pretest probability score, HDAA, and optical density (OD) value was implemented as a tool to assist in the diagnosis of HIT and with the decision to treat patients. Patients with a 4T score >3 and/or positive HDAA result with an OD ≥1 were considered positive. Utilisation of this algorithm was hypothesised to improve the identification of patients without SRA confirmed HIT and improve overall specificity compared to other diagnostic strategies. Retrospective chart review was conducted and included patients with a positive or equivocal HDAA result and a serotonin release assay result during a two-year period. Each patient was evaluated for the diagnosis of HIT using the algorithm. The specificity and sensitivity of the diagnostic algorithm to identify subjects with SRA confirmed HIT was evaluated. A total of 83 patients were identified for inclusion in the study. The diagnostic algorithm identified 22 patients for direct thrombin inhibitor (DTI) therapy. Nine of these patients were SRA positive. The sensitivity of the algorithm was 0.9 with a specificity of 0.822. The diagnostic algorithm was found to be both more specific and sensitive than other diagnostic strategies including the 4T score alone, HDAA alone, and the combination of the 4T score and HDAA results. This preliminary data suggest a diagnostic algorithm combining 4T score, HDAA, and OD value may be a tool to aid in the identification SRA positive patients for DTI therapy.
Extended evidence for association between the melanoma inhibitory activity 3 gene and myocardial infarction
Authors: Schatke Anna , Wolferstetter Hannah , Mueller Jakob , Schömig Albert , Kastrati Adnan , Koch Werner
Published: January 2011

In a genome-wide scan, isolated single nucleotide polymorphisms (SNPs), including rs17465637, in the melanoma inhibitory activity 3 gene (MIA3) on chromosome 1 were identified to be associated with coronary artery disease and myocardial infarction (MI). Because the role of common variation at the MIA3 locus has not yet been investigated, the aim of this case-control study was to determine the impact of haplotype-tagging SNPs and haplotypes in the MIA3 region on the risk of MI. In a set of nine haplotype-tagging SNPs, rs17465637, but none of the other SNPs, was associated with MI. After adjustments were made for age, gender, history of arterial hypertension, history of hyper-cholesterolaemia, current cigarette smoking and diabetes mellitus, multiple logistic regression analyses showed an increased risk in the carriers of one or two C alleles [adjusted odds ratio (OR) 1.17, 95% confidence interval (CI) 1.04–1.32, and 1.37, 95% CI 1.08–1.74, respectively]. Nine common haplotypes (frequency >1%) were established across the MIA3 region. Two of the haplotypes were associated with an increased risk of MI: the frequent (48%) TGACCAAAG haplotype and the rare (2%) CGACCAAAG haplotype (adjusted OR 1.102, 95% CI 1.002–1.212, and 1.574, 95% CI 1.077–2.298, respectively). Showing association between rs17465637 and MI, this work was consistent with results from the original detection study and most prior replication studies addressing this issue. In addition to correspond with such isolated evidence of association with MI, the present study identified specific haplotypes capturing the risk-related variation in the entire MIA3 region.
Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance
Authors: Tosetto Alberto , Federici Augusto , Rodeghiero Francesco , Castaman Giancarlo
Published: January 2011

Accelerated clearance of von Willebrand factor (VWF) has been recently identified as a major pathophysiologic mechanism inducing low VWF in some patients with von Willebrand disease (VWD). The frequency of bleeding and the best treatment of these patients have never been evaluated prospectively in large series of patients. It was the aim of the present study to prospectively evaluate clinical events of 60 heterozygous patients with VWD Vicenza (VWD-VI) carrying R1205H VWF mutation and 23 with C1130F mutation, both characterised by markedly increased VWF clearance. During 71 months of follow-up, 65% of patients with VWD-VI and 61% with C1130F required treatment. The rate of spontaneous bleeding requiring consultation/treatment was 7.5/100 patients-year in patients with C1130F mutation vs. 1.9/100 patients-year in those with R1205H (p=0.004). This difference persisted also by multivariate analysis adjusted for sex, age and blood group (hazard ratio [HR]=3.3 for C1130F, 95% confidence interval [CI] 1.16–9.27) and females were at greater risk of bleeding (HR=3, 95%CI 1.01–9.93) because of menorrhagia. Only 3/15 (20 %) women in fertile age with VWD-VI compared to 8/9 (89 %) with C1130F mutation required consultation/treatment for menorrhagia (iron supplementation, combined oral contraceptives, tranexamic acid). Almost all dental extractions, minor surgeries and deliveries occurring during follow-up were successfully managed with desmopressin. Major surgery required factor VIII/VWF concentrates, but a few cases benefited from desmopressin. In conclusion, similar to patients with type 1 VWD, also in patients with increased VWF clearance desmopressin maintains a major therapeutic role.
Forecasting the Future of Cardiovascular Disease in the United States
Authors: Heidenreich Paul A. , Trogdon Justin G. , Khavjou Olga A. , Butler Javed , Dracup Kathleen , Ezekowitz Michael D. , Finkelstein Eric Andrew , Hong Yuling , Johnston S. Claiborne , Khera Amit , Lloyd-Jones Donald M. , Nelson Sue A. , Nichol Graham , Orenstein Diane , Wilson Peter W.F. , Woo Y. Joseph
Published: January 2011

Background—

Cardiovascular disease (CVD) is the leading cause of death in the United States and is responsible for 17% of national health expenditures. As the population ages, these costs are expected to increase substantially.

Methods and Results—

To prepare for future cardiovascular care needs, the American Heart Association developed methodology to project future costs of care for hypertension, coronary heart disease, heart failure, stroke, and all other CVD from 2010 to 2030. This methodology avoided double counting of costs for patients with multiple cardiovascular conditions. By 2030, 40.5% of the US population is projected to have some form of CVD. Between 2010 and 2030, real (2008$) total direct medical costs of CVD are projected to triple, from $273 billion to $818 billion. Real indirect costs (due to lost productivity) for all CVD are estimated to increase from $172 billion in 2010 to $276 billion in 2030, an increase of 61%.

Conclusions—

These findings indicate CVD prevalence and costs are projected to increase substantially. Effective prevention strategies are needed if we are to limit the growing burden of CVD.
Efficacy of Quantified Home-Based Exercise and Supervised Exercise in Patients With Intermittent Claudication
Authors: Gardner Andrew W. , Parker Donald E. , Montgomery Polly S. , Scott Kristy J. , Blevins Steve M.
Published: January 2011

Background—

This prospective, randomized, controlled clinical trial compared changes in exercise performance and daily ambulatory activity in peripheral artery disease patients with intermittent claudication after a home-based exercise program, a supervised exercise program, and usual-care control.

Methods and Results—

Of the 119 patients randomized, 29 completed home-based exercise, 33 completed supervised exercise, and 30 completed usual-care control. Both exercise programs consisted of intermittent walking to nearly maximal claudication pain for 12 weeks. Patients wore a step activity monitor during each exercise session. Primary outcome measures included claudication onset time and peak walking time obtained from a treadmill exercise test; secondary outcome measures included daily ambulatory cadences measured during a 7-day monitoring period. Adherence to home-based and supervised exercise was similar (
P
=0.712) and exceeded 80%. Both exercise programs increased claudication onset time (
P
<0.001) and peak walking time (
P
<0.01), whereas only home-based exercise increased daily average cadence (
P
<0.01). No changes were seen in the control group (
P
>0.05). The changes in claudication onset time and peak walking time were similar between the 2 exercise groups (
P
>0.05), whereas the change in daily average cadence was greater with home-based exercise (
P
<0.05).

Conclusions—

A home-based exercise program, quantified with a step activity monitor, has high adherence and is efficacious in improving claudication measures similar to a standard supervised exercise program. Furthermore, home-based exercise appears more efficacious in increasing daily ambulatory activity in the community setting than supervised exercise.

Clinical Trial Registration—

URL:
http://www.ClinicalTrials.Gov
. Unique identifier: NCT00618670.
Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction
Authors: Simon Tabassome , Steg Philippe Gabriel , Gilard Martine , Blanchard Didier , Bonello Laurent , Hanssen Michel , Lardoux Hervé , Coste Pierre , Lefèvre Thierry , Drouet Elodie , Mulak Geneviève , Bataille Vincent , Ferrières Jean , Verstuyft Céline , Danchin Nicolas
Published: January 2011

Background—

Clopidogrel requires metabolic activation by cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs.

Methods and Results—

The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08;
P
=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08;
P
=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively.

Conclusion—

PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00673036.
Dexamethasone Arterializes Venous Endothelial Cells by Inducing Mitogen-Activated Protein Kinase Phosphatase-1
Authors: Zakkar Mustafa , Luong Le Anh , Chaudhury Hera , Ruud Oeyvind , Punjabi Prakash P. , Anderson Jon R. , Mullholand John W. , Clements Anne T. , Krams Rob , Foin Nicholas , Athanasiou Thanos , Leen Edward L.S. , Mason Justin C. , Haskard Dorian O. , Evans Paul C.
Published: January 2011

Background—

Vein grafting in coronary artery surgery is complicated by a high restenosis rate resulting from the development of vascular inflammation, intimal hyperplasia, and accelerated atherosclerosis. In contrast, arterial grafts are relatively resistant to these processes. Vascular inflammation is regulated by signaling intermediaries, including p38 mitogen-activated protein (MAP) kinase, that trigger endothelial cell (EC) expression of chemokines (eg, interleukin-8, monocyte chemotactic protein-1) and other proinflammatory molecules. Here, we have tested the hypothesis that p38 MAP kinase activation in response to arterial shear stress (flow) may occur more readily in venous ECs, leading to greater proinflammatory activation.

Methods and Results—

Comparative reverse-transcriptase polymerase chain reaction and Western blotting revealed that arterial shear stress induced p38-dependent expression of monocyte chemotactic protein-1 and interleukin-8 in porcine jugular vein ECs. In contrast, porcine aortic ECs were protected from shear stress–induced expression of p38-dependent chemokines as a result of rapid induction of MAP kinase phosphatase-1. However, we observed with both cultured porcine jugular vein ECs and perfused veins that venous ECs can be protected by brief treatment with dexamethasone, which induced MAP kinase phosphatase-1 to suppress proinflammatory activation.

Conclusions—

Arterial but not venous ECs are protected from proinflammatory activation in response to short-term exposure to high shear stress by the induction of MAP kinase phosphatase-1. Dexamethasone pretreatment arterializes venous ECs by inducing MAP kinase phosphatase-1 and may protect veins from inflammation.
Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction
Authors: Korf-Klingebiel Mortimer , Kempf Tibor , Schlüter Klaus-Dieter , Willenbockel Christian , Brod Torben , Heineke Jörg , Schmidt Volker J. , Jantzen Franziska , Brandes Ralf P. , Sugden Peter H. , Drexler Helmut , Molkentin Jeffery D. , Wollert Kai C.
Published: January 2011

Background—

Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart.

Methods and Results—

We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice.

Conclusions—

Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.
Dietary Iron Restriction Prevents Hypertensive Cardiovascular Remodeling in Dahl Salt-Sensitive Rats
Authors: Naito Yoshiro , Hirotani Shinichi , Sawada Hisashi , Akahori Hirokuni , Tsujino Takeshi , Masuyama Tohru
Published: January 2011

Iron accumulation is associated with the pathogenesis of several cardiovascular diseases. However, the preventive effects of iron restriction (IR) against cardiovascular disease remain obscure. We investigated the effects of dietary IR on cardiovascular pathophysiology and the involved mechanism in Dahl salt-sensitive rats. Dahl salt-sensitive rats were provided either a normal or high-salt (HS) diet. Another subset of Dahl salt-sensitive rats were fed an HS with iron-restricted (HS+IR) diet for 11 weeks. Dahl salt-sensitive rats given an HS diet developed hypertension, heart failure, and decreased a survival rate after 11 weeks on the diet. In contrast, IR attenuated the development of hypertension and heart failure, thereby improving survival rate. Dietary IR suppressed cardiovascular hypertrophy, fibrosis, and inflammation in HS rats. The phosphorylation of Akt, AMP-activated protein kinase, and endothelial nitric oxide synthase was decreased in the aorta of HS rats, whereas they were ameliorated by the IR diet. Aortic expression of the cellular iron import protein transferrin receptor 1, and the iron storage protein ferritin H-subunit, was upregulated in HS rats. IR also attenuated proteinuria and increased oxidative stress in the HS group.
N
G
-nitro-
l
-arginine methyl ester abolished the beneficial effects of IR and decreased survival rate in HS+IR rats. Dietary IR had protective effects on salt-induced hypertension, cardiovascular remodeling, and proteinuria through the inhibition of oxidative stress, and maintenance of Akt, AMP-activated protein kinase, and endothelial nitric oxide synthase in the aorta. IR could be an effective strategy for prevention of HS-induced organ damage in salt-sensitive hypertensive patients.