bluuebunny/crossref_metadata_2025 huggingface dataset:
NetPilot
Authors: Wu Xin , Turner Daniel , Chen Chao-Chih , Maltz David A. , Yang Xiaowei , Yuan Lihua , Zhang Ming
Published: September 2012

Driven by the soaring demands for always-on and fast-response online services, modern datacenter networks have recently undergone tremendous growth. These networks often rely on commodity hardware to reach immense scale while keeping capital expenses under check. The downside is that commodity devices are prone to failures, raising a formidable challenge for network operators to promptly handle these failures with minimal disruptions to the hosted services.

Recent research efforts have focused on automatic failure localization. Yet, resolving failures still requires significant human interventions, resulting in prolonged failure recovery time. Unlike previous work, NetPilot aims to quickly
mitigate
rather than resolve failures. NetPilot mitigates failures in much the same way operators do -- by deactivating or restarting suspected offending components. NetPilot circumvents the need for knowing the exact root cause of a failure by taking an intelligent trial-and-error approach. The core of NetPilot is comprised of an Impact Estimator that helps guard against overly disruptive mitigation actions and a failure-specific mitigation planner that minimizes the number of trials. We demonstrate that NetPilot can effectively mitigate several types of critical failures commonly encountered in production datacenter networks.
The anatomy of a large mobile massively multiplayer online game
Authors: Patro Ashish , Rayanchu Shravan , Griepentrog Michael , Ma Yadi , Banerjee Suman
Published: September 2012

We describe a large-scale and long-term measurement study of a popular mobile Massively Multiplayer Online Role Playing Game (MMORPG), called Parallel Kingdom, which has over 600,000 unique users distributed across more than 100 countries. Our study covers important aspects of the game including (i) characteristics of its population, (ii) players' game usage behavior, and (iii) correlation between players' interest and the money spent by them in the game. Our measurement study spans almost the entire life of the game staring from its inception on October 31, 2008 to November 10, 2011 (1104 days in total). To perform this study, we instrumented the game's client software (iOS and Android) to interact with our measurement server. The rich dataset gathered allowed us to analyze various characteristics of this highly popular mobile MMORPG.
Up, down and around the stack
Authors: Bischof Zachary S. , Otto John S. , Bustamante Fabián E.
Published: September 2012

Broadband characterization has recently attracted much attention from the research community and the general public. Given this interest and the important business and policy implications of residential Internet service characterization, recent years have brought a variety of approaches to profiling Internet services, ranging from Web-based platforms to dedicated infrastructure inside home networks. We have previously argued that network-intensive applications provide an almost ideal vantage point for broadband service characterization at sufficient scale, nearly continuously and from end users. While we have shown that the approach is indeed effective at characterization and can enable performance comparisons between service providers and geographic regions, a key unanswered question is how well the performance characteristics captured by these network-intensive applications can predict the overall user experience with other applications.

In this paper, using BitTorrent as an example network-intensive application, we present initial results that demonstrate how to obtain estimates of bandwidth and latency of a network connection by leveraging passive monitoring and limited active measurements from network intensive applications. We then analyze user experienced web performance under a variety of network conditions and show how estimated metrics from this network intensive application can serve as good web performance predictors.
Measuring the perceptual quality of Skype sources
Authors: Chen Chien-nan , Chu Cing-yu , Yeh Su-ling , Chu Hao-hua , Huang Polly
Published: September 2012

The success of Skype has inspired a generation of peer-to-peer-based solutions for real-time multimedia services over the Internet. However, there lacks still a robust metric quantifying the perceptual quality of a Skype call. The widely-used PESQ (Perceptual Evaluation of Speech Quality) falls short of modeling super-wideband calls, which are characteristics of SILK Skype's codec made public in 2011. Towards a robust QoE (Quality of Experience) metric for VoIP call analysis, we propose a model, referred to as WF-Regression model, to capture the call rate and perceptual quality relationship. The model is shown through a user study that it is robust, R-square = 0.9990 and outperform PESQ modeling the quality of Skype calls, error ratio = 3.68% vs. 14.59%.
Skin-Test Infiltrating Lymphocytes Early Predict Clinical Outcome of Dendritic Cell–Based Vaccination in Metastatic Melanoma
Authors: Aarntzen Erik H.J.G. , Bol Kalijn , Schreibelt Gerty , Jacobs Joannes F.M. , Lesterhuis W. Joost , Van Rossum Michelle M. , Adema Gosse J. , Figdor Carl G. , Punt Cornelis J.A. , De Vries I. Jolanda M.
Published: September 2012

The identification of responding patients early during treatment would improve the capability to develop effective new immunotherapies more rapidly. Here, we describe a bioassay that may link early T-cell–mediated immune responses to later clinical benefits. This bioassay rests upon the tenet of immunotherapy that tumor-specific effector T cells capable of invading peripheral tissue can recognize tumor antigens and exert cytotoxic functions there. To show its utility, we conducted a retrospective study of a large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic cell (DC)-based vaccination protocols to examine a hypothesized correlation of posttreatment skin-infiltrating lymphocytes (SKIL) with overall survival (OS). Stringent immunologic criteria were defined to identify long-term survivors. The presence of tumor-associated antigen (TAA)-specific CD8+ T cell populations within SKILs (criterion I) was highly predictive for long-term survival. Further restriction by selecting for the presence of TAA-specific CD8+ T cells specifically recognizing tumor peptide (criterion II) was also associated with improved OS. Recognition of naturally processed antigen (criterion III) maximized the accuracy of the test, with a median OS of 24.1 versus 9.9 months (P = 0.001). Our results show that detailed characterization of SKILs can permit an accurate selection of metastatic melanoma patients who benefit most from DC-based vaccination. This simple and robust bioassay integrates multiple aspects of cellular functions that mediate effective immune responses, thereby offering an effective tool to rapidly identify patients who are responding to immunotherapy at an early stage of treatment. Cancer Res; 72(23); 6102–10. ©2012 AACR.
Prostate Cancer Mortality following Active Surveillance versus Immediate Radical Prostatectomy
Authors: Xia Jing , Trock Bruce J. , Cooperberg Matthew R. , Gulati Roman , Zeliadt Steven B. , Gore John L. , Lin Daniel W. , Carroll Peter R. , Carter H. Ballentine , Etzioni Ruth
Published: September 2012

Propose: Active surveillance has been endorsed for low-risk prostate cancer, but information about long-term outcomes and comparative effectiveness of active surveillance is lacking. The purpose of this study is to project prostate cancer mortality under active surveillance followed by radical prostatectomy versus under immediate radical prostatectomy.

Experimental design: A simulation model was developed to combine information on time from diagnosis to treatment under active surveillance and associated disease progression from a Johns Hopkins active surveillance cohort (n = 769), time from radical prostatectomy to recurrence from cases in the CaPSURE database with T-stage ≤ T2a (n = 3,470), and time from recurrence to prostate cancer death from a T-stage ≤ T2a Johns Hopkins cohort of patients whose disease recurred after radical prostatectomy (n = 963). Results were projected for a hypothetical cohort aged 40 to 90 years with low-risk prostate cancer (T-stage ≤ T2a, Gleason score ≤ 6, and prostate-specific antigen level ≤ 10 ng/mL).

Results: The model projected that 2.8% of men on active surveillance and 1.6% of men with immediate radical prostatectomy would die of their disease in 20 years. Corresponding lifetime estimates were 3.4% for active surveillance and 2.0% for immediate radical prostatectomy. The average projected increase in life expectancy associated with immediate radical prostatectomy was 1.8 months. On average, the model projected that men on active surveillance would remain free of treatment for an additional 6.4 years relative to men treated immediately.

Conclusions: Active surveillance is likely to produce a very modest decline in prostate cancer-specific survival among men diagnosed with low-risk prostate cancer but could lead to significant benefits in terms of quality of life. Clin Cancer Res; 18(19); 5471–8. ©2012 AACR.
Food-Cooking Processes Modulate Allergenic Properties of Hen’s Egg White Proteins
Authors: Liu Xiaoyu , Feng Bai-Sui , Kong Xiaoli , Xu Hong , Li Xiumin , Yang Ping-Chang , Liu Zhigang
Published: September 2012

Background and Objective: Reducing the allergenicity of food allergens can suppress the clinical symptoms of food allergy. The objective of the present study was to investigate the effects of processing on the allergenic properties of hen’s egg white proteins. Methods: Eggs were processed by traditional Chinese cooking, including steaming, water boiling, frying, spicing and tea boiling. The contents of processed egg protein were assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis; the allergenicity was evaluated by Western blotting, enzyme-linked immunosorbent assay and enzyme allergosorbent test inhibition. Circular dichroism spectrum analysis of four major egg allergens from various egg products was performed as well. A mouse model of food allergy was developed to test the allergenicity of processed egg protein in vivo. Results: Protein degradation was significant following tea boiling and spiced-tea boiling. The total allergenic potential of water-boiled egg and fried egg was relatively higher than that of steamed egg, spiced egg and tea-boiled egg. Challenge with proteins from raw egg, water-boiled egg and fried egg induced skewed T-helper 2 pattern responses (Th2 responses) in the intestine of mice sensitized to egg proteins; however, when the mice sensitized to egg proteins were challenged with proteins from steamed egg, spiced egg and tea-boiled egg, respectively, only weak Th2 responses were induced in their intestine. Conclusion: Processing by steaming, spicing, or tea boiling can weaken the allergenicity of egg proteins.
Maternal Hemodynamics at 11–13 Weeks of Gestation in Pregnancies Delivering Small for Gestational Age Neonates
Authors: Khalil A. , Sodre D. , Syngelaki A. , Akolekar R. , Nicolaides K.H.
Published: September 2012

Objective: To examine aortic systolic blood pressure (SBPAo), pulse wave velocity (PWV) and augmentation index (adjusted to a heart rate of 75 beats per minute, AIx-75) at 11–13 weeks’ gestation in pregnancies delivering small for gestational age (SGA) neonates with and without preeclampsia (PE). Methods: At 11+0 to 13+6 weeks’ gestation, maternal history was recorded and PWV, AIx-75, SBPAo, uterine artery pulsatility index (PI) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) were measured. We compared women with (n = 337) and without (n = 48) PE that delivered SGA neonates with unaffected controls (n = 6,429). Results: In the SGA group without PE, compared to unaffected controls, there was no significant difference in AIx-75 (1.03 vs. 1.00 multiple of the median, MoM), PWV (0.98 vs. 1.00 MoM) or SBPAo (1.01 vs. 1.00 MoM), but uterine artery PI was increased (1.10 vs. 1.00 MoM) and PAPP-A decreased (0.85 vs. 1.00 MoM). In SGA with PE, compared to unaffected controls, there was increased AIx-75 (1.13 vs. 1.00 MoM), SBPAo (1.09 vs. 1.00 MoM), uterine artery PI (1.40 vs. 1.00 MoM) and decreased PAPP-A (0.72 vs. 1.00 MoM), but no significant difference in PWV (1.05 vs. 1.00 MoM). Conclusion: In pregnancies with SGA neonates, impaired placentation is reflected in low PAPP-A and high uterine artery PI at 11–13 weeks’ gestation. In the SGA group with PE, but not in those without PE, there is increased SBPAo and AIx-75.
Matrix Metalloproteinase-9 Increases in the Sputum from Allergic Occupational Asthma Patients after Specific Inhalation Challenge
Authors: Castano Roberto , Miedinger David , Maghni Karim , Ghezzo Heberto , Trudeau Carole , Castellanos Lucero , Wattiez Mathieu , Vandenplas Olivier , Malo Jean-Luc
Published: September 2012

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a role in the pathogenesis of asthma. MMP-9 increases in the sputum of asthmatic patients after bronchial challenge with common allergens. We sought to assess whether a high-molecular-weight occupational allergen was able to induce changes in MMP-9 as well as in other MMPs and TIMPs in subjects with occupational asthma. Methods: Ten patients underwent specific inhalation challenge (SIC) on 2 consecutive days. We monitored changes in lung function by measuring FEV1 for 7 h. Induced sputum test was performed at 6 h after sham and flour challenge. The total and differential cell counts were analyzed. Levels of MMPs (specifically MMP-2, MMP-7, MMP-9 and MMP-13) were measured using Fluorokine® MultiAnalyte Profiling kits and a Luminex® Bioanalyzer, while levels of TIMP-1 and TIMP-2 were measured by ELISA. Results: Flour challenge increased the percentage of eosinophils in sputum samples. Asthmatic reactions induced by flour were associated with a significant increase in the sputum level of MMP-9 (p = 0.05), but not in the levels of MMP-2, MMP-7, MMP-13, TIMP-1 and TIMP-2. Sputum levels of MMP-9 measured after flour challenge were nearly significantly correlated (r = 0.67; p = 0.06) with the maximal fall in FEV1 observed during the asthmatic reaction, but they did not correlate with the number of neutrophils (r = 0.18; p = 0.7) and eosinophils (r = 0.55; p = 0.2). Conclusions: This study showed that MMP-9 increases in sputum samples from sensitized occupational asthma patients after SIC with flour.
Differences in Systemic and Skin Migrating-Specific CD4+ T Cells in Papular Urticaria by Flea Bite
Authors: Dominguez-Amorocho Omar , Duarte Silvia , González John Mario , Halpert Evelyne , Ortega María Claudia , Rodríguez Adriana , García Elizabeth , Cuellar Adriana
Published: September 2012

Background: Papular urticaria by flea bite is a chronic allergic condition in which clinical improvement may occur at the age of 7 years, thus representing a natural model of acquired immunologic tolerance in humans. The aim of this study was to characterize regulatory cells and specific responses to flea antigens of CD4+ T lymphocytes expressing cutaneous migration markers in patients with papular urticaria caused by flea bite and with different disease evolution times. Methods: Cell populations were characterized by flow cytometry in samples from patients and healthy controls. Specific cell stimulation was performed with a complete flea body extract. The Mann-Whitney U test was used for comparisons. Results: Total dendritic cells were lower in patients than in healthy controls. No quantitative differences were found in CD4 regulatory T cells. CD4+ T cells from patients produced more IL-4, lL-10, IL-17, and IFN-γ. Patients who experienced the onset of symptoms within the first 5 years of age showed a greater percentage of local (cutaneous lymphocyte antigen +) IL-4- and IL-17-producing cells, while patients who experienced the onset of symptoms after the age of 5 years had a higher percentage of systemic (cutaneous lymphocyte antigen –) IL-10-producing cells. Conclusion: Analysis of the cellular immune response against whole flea antigen in patients with papular urticaria by flea bites suggests a possible participation of inflammatory cytokines in the skin reaction (Th17) and a systemic control mechanism (IL-10). This pattern of cytokine production in patients could be a consequence of an impaired dendritic cell population.
Usefulness and Limitations of Sequential Serum Tryptase for the Diagnosis of Anaphylaxis in 102 Patients
Authors: Sala-Cunill Anna , Cardona Victoria , Labrador-Horrillo Moises , Luengo Olga , Esteso Olga , Garriga Teresa , Vicario Maria , Guilarte Mar
Published: September 2012

Background: The diagnosis of anaphylaxis is based on clinical history since no reliable biological marker is currently available to confirm the diagnosis. Objective: It was the aim of this study to determine sequential serum tryptase concentrations during anaphylaxis and to evaluate its potential as a diagnostic marker. Methods: We performed a prospective study including patients with acute anaphylaxis (according to the National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria) attending the emergency department. Demographic characteristics, anaphylactic triggers, specific risk factors, clinical characteristics and management of anaphylaxis were recorded. Serum tryptase was measured at 1–2 h (T1), 4–6 h (T2) and 12–24 h (T3) following onset of the episode and at basal conditions (TB). Results: A total of 102 patients were included (63 females, mean age 47.4 ± 19.1 years). Tryptase concentration at T1 (19.3 ± 15.4 µg/l) was significantly higher than at T2, T3 and TB (all <11.4 µg/l; p < 0.0001). Importantly, tryptase was not raised in 36.3% of cases; furthermore, in 60.6% of these patients, no changes were observed in tryptase levels comparing T1 and TB (ΔT1–TB = 0). Tryptase was more frequently elevated in more severe anaphylaxis (p < 0.0001) and positively correlated with the grades of severity (p < 0.001, r = 0.49). Anaphylaxis was more severe and tryptase concentration higher when the causative agent was a drug compared to food, both at T1 (p = 0.045) and at TB (p = 0.019). Age and coronary risk factors were associated with more severe anaphylaxis (p = 0.001). Conclusion: Tryptase is a biomarker related to the severity of anaphylaxis. However, since its concentration remains unaltered in a considerable number of patients during acute anaphylaxis, there is a need for more reliable diagnostic biological tests.
Successful Desensitization to Imiglucerase of an Adult Patient Diagnosed with Type I Gaucher Disease
Authors: Erdoğdu Derya , Gelincik Aslı , Canbaz Bülent , Colakoğlu Bahattin , Büyüköztürk Suna , Tanakol Refik
Published: September 2012

Gaucher disease is the most common lysosomal storage disorder, and enzyme replacement therapy, such as administration of imiglucerase, is the standard therapy. Anaphylaxis to imiglucerase is rarely reported. Here, we report a 26-year-old female who was diagnosed with type 1 Gaucher disease and referred to our Allergy Outpatient Clinic because of an anaphylactic reaction due to imiglucerase enzyme therapy. A desensitization protocol was administered with two different dilutions with an increasing rate of administration delivered in 10 consecutive steps by intravenous infusion in an intensive care setting. No reactions occurred during the procedure, and the total final dose of 2,000 U was successfully administered. To our knowledge, this is the first adult case with successful desensitization to imiglucerase. Desensitization protocols to drugs in chronic disease patients for whom no alternative therapies are available can be lifesaving.
Prevalence of Allergic Sensitization versus Allergic Rhinitis Symptoms in an Unselected Population
Authors: Blomme Katrien , Tomassen Peter , Lapeere Hilde , Huvenne Wouter , Bonny Michiel , Acke Frederic , Bachert Claus , Gevaert Philippe
Published: September 2012

Background: Allergic rhinitis (AR) is the most common allergic disorder and its prevalence has significantly increased worldwide, nowadays affecting up to 40% of the population in young adults. The objective of the present survey was to evaluate the prevalence of allergic sensitization and the prevalence of clinically diagnosed AR in a sample of the Belgian population, and to estimate the effect of age and gender. Methods: We performed a cross-sectional population-based study at an annual public fair in Ghent. Participants underwent a skin prick test (SPT) to 3 aeroallergens: a mix of trees (hazel, alder, and birch), grass pollen, and house dust mite (HDM). The clinical relevance of sensitization was assessed by relating relevant symptoms of AR to the corresponding SPT. Results: A total of 2,320 participants (1,475 females, median age 44.7 years, range 3–86) were included in this study. The standardized prevalence rates of sensitization were 13.2% for tree mix, 25.9% for grass pollen, and 25.9% for HDM. Sensitization to at least one of the allergens was present in 40.3% of the subjects. Symptomatic sensitization related to trees was reported in 9.7% of cases, grass-related AR was 17.6%, and HDM-related AR was 17.1%. The overall prevalence of AR was 30.9%. Conclusion: In this study we demonstrated a 40.3% prevalence of a positive SPT to one or more common aeroallergens. A clinical diagnosis of AR was present in 30.9% of cases, peaking in the third and fourth decades of life. It is to be expected that in the next decades, when this generation grows older, the general AR prevalence will further increase.
Cytokine Secretion from Human Monocytes Potentiated by P-Selectin-Mediated Cell Adhesion
Authors: Suzuki Junsuke , Hamada Eri , Shodai Tomonori , Kamoshida Go , Kudo Sanae , Itoh Saotomo , Koike Junzo , Nagata Kisaburo , Irimura Tatsuro , Tsuji Tsutomu
Published: September 2012

Background/Aim: P-selectin is a carbohydrate-recognizing cell adhesion molecule expressed on activated platelets and endothelial cells. It plays a crucial role in the recruitment of leukocytes to inflammatory and hemorrhagic sites. Cell adhesion mediated by P-selectin induces leukocyte activation, such as the generation of reactive oxygen species and the expression of blood coagulation factors. We assessed how P-selectin-mediated cell adhesion affects cytokine secretion from monocytes. Methods: Human peripheral blood monocytes were cultured in a plate that had been coated with P-selectin purified from human platelets, and cytokines released in the culture supernatant from monocytes were determined by ELISA. Results: The secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-12 and macrophage inflammatory protein-1β increased 3- to 10-fold in response to P-selectin compared with unstimulated monocytes. We next examined the effects of cytokine treatment of monocytes on their susceptibility to P-selectin. The secretion of TNF-α from monocytes in response to P-selectin was increased when monocytes were preincubated with granulocyte/macrophage colony-stimulating factor, monocyte chemotactic protein-1 or interferon-γ (IFN-γ); IFN-γ was the most effective in potentiating TNF-α secretion from monocytes. Conclusion: These results suggest that the interaction of monocytes with P-selectin plays an important role not only in their trafficking but also in the regulation of cytokine production by these cells.
Ceramide Expression and Cell Homeostasis in Chronic Obstructive Pulmonary Disease
Authors: Scarpa Maria C. , Baraldo Simonetta , Marian Emanuela , Turato Graziella , Calabrese Fiorella , Saetta Marina , Maestrelli Piero
Published: September 2012

Background: Increased expression of ceramide has been detected in emphysema. Ceramide promotes autophagy and apoptosis, which concur with cellular homeostasis. Objectives: To determine whether ceramide expression is associated with the development of chronic obstructive pulmonary disease (COPD) and with altered cellular homeostasis in lung parenchyma. Methods: We studied 10 subjects with severe COPD, 13 with mild/moderate COPD, 11 with idiopathic pulmonary fibrosis (IPF), 12 non-COPD smokers, and 11 nonsmoking controls. The immunoreactivity for ceramide along with markers of autophagy (LC3B), apoptosis (cleaved caspase-3), and cell proliferation (MIB1) was quantified in alveolar walls. Results: Ceramide expression was increased in COPD patients compared with control smokers and was related to the impairment of gas exchange but not to the degree of airflow limitation. In COPD, an important activation of apoptosis and autophagy pathways was observed, particularly in patients with severe disease, that was not counterbalanced by cell proliferation. Upregulation of ceramide was observed even in subjects with IPF in whom activation of apoptosis and autophagy was negligible and cell proliferation was instead the most prominent feature. Conclusions: Ceramide expression, which is increased in COPD and even more so in IPF, appears to be neither specific nor related to COPD severity, probably representing a broader marker of lung damage. In contrast, apoptosis and autophagy are characteristics of the COPD pathology, particularly in its most severe stage.
Biphasic Late Airway Hyperresponsiveness in a Murine Model of Asthma
Authors: Kim Hae-Kyoung , Lee Chang-Hoon , Kim Jun-Mo , Ayush Otgonzaya , Im Suhn-Yong , Lee Hern-Ku
Published: September 2012

Background: Nonspecific airway hyperresponsiveness (AHR) is one of the cardinal features of bronchial asthma. Early AHR is caused by chemical mediators released from pulmonary mast cells activated in an IgE-dependent way. However, the mechanism of late AHR remains unclear. Methods: Features of airway allergic inflammation were analyzed, including antigen-induced AHR, using a murine model of asthma. The model was suitable for examining the sequential early molecular events occurring after the initial airway exposure to antigen. Results: AHR increased at 10–12 h after airway challenge, followed by the second-phase response, which was larger and broader in resistance at 18–30 h. Pretreatment of sensitized animals with anti-tumor necrosis factor (TNF) before airway challenge or induction of allergic asthma in TNF–/– mice resulted in abrogation of the first-phase late AHR. Intratracheal instillation of TNF induced a single peak of AHR at 10 h. IgE and IgG immune complexes induced the development of the first-phase late AHR by TNF production. Pretreatment with cytosolic phospholipase inhibitor and 5-lipoxygenase inhibitors abolished the first-phase late AHR as well as the leukotriene B4 levels in the airway. CpG-oligodeoxynucleotide (ODN) pretreatment reduced airway levels of Th2 cytokines, eosinophil infiltration and second-phase late AHR. However, CpG-ODN did not reduce TNF levels or the magnitude of first-phase late AHR. Conclusion: Biphasic late AHR occurs in a murine model of asthma. First- and second-phase late AHR is caused by TNF and Th2 response, respectively.
Glycated Albumin Is Superior to Hemoglobin A1c for Evaluating the Presence and Severity of Coronary Artery Disease in Type 2 Diabetic Patients
Authors: Shen Ying , Pu Li Jin , Lu Lin , Zhang Qi , Zhang Rui Yan , Shen Wei Feng
Published: September 2012

Objectives: This study aimed to compare the value of serum glycated albumin (GA) level versus glycated hemoglobin A1c (HbA1c) for evaluating the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). Methods: Serum GA and blood HbA1c levels were measured in 829 consecutive T2DM patients with or without angiographically documented significant CAD (≥70% diameter stenosis). Results: Serum GA levels were higher in diabetic patients with significant CAD than in those without (20.57 ± 4.23 vs. 19.00 ± 4.48%; p < 0.001), but HbA1c was similar in the two groups (7.74 ± 1.34 vs. 7.51 ± 1.37% p > 0.05). Compared to HbA1c, GA correlated more closely with the sum of significant stenotic lesions (r = 0.275, p < 0.001 and r = 0.092, p = 0.019) and the extent index (r = 0.375, p < 0.001 and r = 0.091, p = 0.019). The area under the curve of GA was larger than that of HbA1c for detecting the presence of significant CAD (0.637 vs. 0.568; p = 0.046) and 3-vessel disease (0.620 vs. 0.536; p = 0.039). GA, but not HbA1c, was independently associated with significant CAD. Conclusions: Serum GA level is a better indicator than HbA1c for evaluating the presence and severity of CAD and predicting major adverse cardiac events in patients with T2DM.
Clinical Management of Patients with a History of Urticaria/Angioedema Induced by Multiple NSAIDs: An Expert Panel Review
Authors: Asero Riccardo , Bavbek Sevim , Blanca Miguel , Blanca-Lopez Natalia , Cortellini Gabriele , Nizankowska-Mogilnicka Ewa , Quaratino Donato , Romano Antonino , Sanchez-Borges Mario , Torres-Jaen Maria Josè
Published: September 2012

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most frequent causes of drug-induced urticaria/angioedema worldwide. Recent review articles have classified patients experiencing NSAID-induced urticaria/angioedema into different categories, including single reactors, multiple reactors, and multiple reactors with underlying chronic urticaria. Each of these categories requires a different clinical approach. The present article, written by a panel of experts, reports the main recommendations for the practical clinical management of patients with a history of urticaria/angioedema induced by multiple NSAID based on current knowledge.
Possible Mechanical Roles of Glycosaminoglycans in Thoracic Aortic Dissection and Associations with Dysregulated Transforming Growth Factor-β
Authors: Humphrey J.D.
Published: September 2012

Background: Four distinguishing histopathological characteristics of thoracic aortic aneurysms and dissections (TAADs) are the fragmentation or degradation of elastic fibers, loss of smooth muscle, pooling of glycosaminoglycans, and remodeling of fibrillar collagens. Of these, pooling of glycosaminoglycans appears to be unique to these lesions. Methods: This review acknowledges the importance of dysregulated transforming growth factor-β (TGF-β) in TAADs and offers a complementary hypothesis that increased TGF-β could contribute to the accumulation of glycosaminoglycans in the media of the proximal thoracic aorta. Regardless, observed pools of glycosaminoglycans could decrease tensile strength, cause stress concentrations, and increase intralamellar swelling pressure, all of which could initiate local delaminations that could subsequently propagate as dissections and result in a false lumen or rupture. Conclusions: There is a pressing need to investigate potential mechanical as well as biological consequences of accumulated glycosaminoglycans in TAADs and to elucidate responsible signaling pathways, with particular attention to synthetic cells of nonmesodermal lineage. Such research could provide insight into the mechanisms of dissection and the seemingly paradoxical role of the over-expression of a cytokine that is typically associated with fibrosis but is implicated in a degenerative disease of the aorta that can result in a catastrophic mechanical failure.
Clopidogrel Two Doses Comparative 1-Year Assessment of Safety and Efficacy (COMPASS) Study in Japanese Patients with Ischemic Stroke
Authors: Uchiyama Shinichiro , Tanahashi Norio , Minematsu Kazuo ,   on behalf of the COMPASS (SFY6913) Study Group
Published: September 2012

Background: Clopidogrel 75 mg once daily is licensed in Japan for the prevention of recurrent ischemic cerebrovascular events in adults as the usual dosage. However, a lower dose (50 mg) is an option in patients at an increased risk of bleeding depending on age, body weight and symptoms. This study compared the safety of both 75- and 50-mg doses of clopidogrel in patients with noncardioembolic ischemic stroke. Methods: This was a double-blind, double-dummy postmarketing clinical trial carried out across 118 Japanese institutions. Patients with an episode of noncardioembolic ischemic stroke at least 8 days prior to randomization, who were aged <75 years or had a body weight >50 kg were randomized to 50 or 75 mg clopidogrel once daily for 52 weeks. The primary endpoint was the incidence of bleeding adverse events. The secondary safety endpoints included the incidence of serious adverse events, serious bleeding adverse events and other prespecified adverse events. The secondary efficacy endpoint was the incidence of vascular events, including ischemic stroke, myocardial infarction, and peripheral artery disease. Results: A total of 1,110 patients were randomized to clopidogrel 50 mg (n = 558) or 75 mg (n = 552). No significant difference between the groups was detected in the incidence of bleeding adverse events, which was 14.0 and 16.5% in the clopidogrel 50- and 75-mg groups, respectively (hazard ratio = 0.831, 95% CI = 0.615–1.124, p = 0.2274). Additionally, there was no statistical difference with respect to any of the secondary safety endpoints. No significant difference between the groups was detected in the incidence of serious adverse events, which was 8.6 and 9.5% in the clopidogrel 50- and 75-mg groups, respectively (hazard ratio = 0.877, 95% CI = 0.597–1.289, p = 0.5035), and there was no significant difference between the groups in the incidence of serious bleeding events, which was 1.7 and 1.5% in the clopidogrel 50- and 75-mg groups, respectively (hazard ratio = 1.240, 95% CI = 0.489–3.142, p = 0.6496). The percentages of intracranial hemorrhage in the 50- and 75-mg groups were 0.18% (1/558) and 0.18% (1/552), respectively. The cumulative incidence of vascular events was somewhat lower in the 75-mg group, but was not statistically different (2.6 vs. 3.8%; p = 0.4118). Conclusions: Clopidogrel 75 mg provides a clinically acceptable safety profile and suggests better clinical benefit as compared to clopidogrel 50 mg for the secondary prevention of ischemic stroke in Japanese patients who are <75 years old with a body weight >50 kg, considering the balance of safety and efficacy on this trial.
Association of Myocardial Deformation With Outcome in Asymptomatic Aortic Stenosis With Normal Ejection Fraction
Authors: Yingchoncharoen Teerapat , Gibby Conrad , Rodriguez L. Leonardo , Grimm Richard A. , Marwick Thomas H.
Published: September 2012

Background—

Current guidelines recommend intervention for symptomatic aortic stenosis, but the management of asymptomatic aortic stenosis remains controversial. As left ventricular global longitudinal strain (GLS) has been shown to predict cardiovascular outcome, we sought to find whether its use could guide the assessment of risk in these patients.

Methods and Results—

We prospectively followed 79 patients with severe asymptomatic aortic stenosis (39 men; mean age, 77 ± 12 years; aortic valve [AV] area index, 0.36 cm
2
/m
2
). In addition to standard echocardiography, speckle strain was measured to assess GLS. Patients were followed for cardiac death and AV replacement driven by symptom development. A multivariable Cox regression was performed to identify associations with events. During 23 ± 20 months, 3 patients had cardiac death and 49 underwent AV replacement. Event-free survival was 72 ± 5% at 1 year, 50 ± 5% at 2 years, and 24 ± 5% at 4 years. Death and AV replacement were predicted by GLS (hazard ratio [HR], 1.14 [95% CI, 1.01–1.28];
P
=0.037), as well as extent of AV calcification (HR, 2.44 [95% CI, 1.17–5.12];
P
=0.018), peak transaortic pressure gradient (HR, 1.03 [95% CI, 1.01–1.04];
P
<0.001), valvulo-arterial impedance (HR, 1.32 [95% CI, 1.04–1.67];
P
=0.045), and Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality (HR, 0.95 [95% CI, 0.90–1.00];
P
=0.052). A mean absolute GLS <15% was associated with a significant excess mortality, and this measurement added incremental prognostic value to the Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality, transaortic peak pressure gradient, AV calcification, and valvulo-arterial impedance.

Conclusions—

GLS is associated with outcomes in patients with severe asymptomatic aortic stenosis, incremental to other clinical and echocardiographic variables.
Use of a Novel Endoscopic Catheter for Direct Visualization and Ablation in an Ovine Model of Chronic Myocardial Infarction
Authors: Betensky Brian P. , Jauregui Miguel , Campos Bieito , Michele John , Marchlinski Francis E. , Oley Leslie , Wylie Bryan , Robinson David , Gerstenfeld Edward P.
Published: September 2012

Background—

Defining the arrhythmogenic substrate is essential for successful ablation of scar-related ventricular tachycardia. The visual characteristics of endocardial ischemic scar have not been described in vivo. The goal of this study was (1) to quantify the visual characteristics of normal tissue, scar border zone, and dense scar in vivo with the use of a novel endoscopic catheter that allows direct endocardial visualization and (2) to correlate visual attributes of myocardial scar with bipolar voltage.

Methods and Results—

Percutaneous transient balloon occlusion (150 minutes) of the mid left anterior descending coronary artery was performed in an ovine model. Animals survived for 41.5±0.7 days. Detailed bipolar voltage maps of the left ventricle were acquired with the use of NavX. Video snapshots of the endocardium were acquired at sites distributed throughout the left ventricle. Visual tissue characteristics of normal (>1.5 mV), border (0.5–1.5 mV), and dense scar (<0.5 mV) were quantified with the use of image processing. Radiofrequency lesions (10–20 W, 30 seconds) were delivered under direct visualization. Mean white-threshold pixel area was lowest in normal tissue (189 969±41 478 pixels
2
), intermediate in scar border zone (255 979±36 016 pixels
2
), and highest in dense scar (324 452±30 152 pixels
2
;
P
<0.0001 for all pairwise comparisons). Tissue whiteness, characteristic of scar, was inversely correlated with bipolar voltage (
P
<0.0001). During radiofrequency lesions, there was a significant increase in white-thresholded pixel area of the visual field after ablation (average increase, 85 381±52 618 pixels
2
;
P
<0.001).

Conclusions—

Visual characteristics of chronic infarct scar in vivo observed with the use of a novel endoscopic catheter correlate with bipolar electrogram voltage. Irrigated radiofrequency lesions in normal endocardial tissue and postinfarction zone can be visualized and quantified with the use of image processing. This technology shows promise for visually based delivery of radiofrequency lesions for the treatment of scar-based ventricular tachycardia.
Preeclampsia Is Characterized by Placental Complement Dysregulation
Authors: Buurma Aletta , Cohen Danielle , Veraar Kimberley , Schonkeren Dorrith , Claas Frans H. , Bruijn Jan A. , Bloemenkamp Kitty W. , Baelde Hans J.
Published: September 2012

Increasing evidence suggests that preeclampsia is associated with complement dysregulation. The origin of complement dysregulation in preeclampsia is unknown, and further unraveling this mechanism could provide both diagnostic tools and therapeutic targets. Because the placenta is believed to play a crucial role in the pathogenesis of preeclampsia, we investigated placentas from preeclamptic women (n=28) and controls (n=44) for the presence of complement activation products. Immunohistochemistry was performed for C1q, mannose-binding lectin, properdin, and C4d. Staining patterns were related to pregnancy outcome. Possible causes of complement activation were investigated, including the presence of immune deposits at the syncytiotrophoblast and changes in the placental mRNA expression of complement regulatory proteins. C4d was rarely present in placentas from healthy controls (3%), whereas it was observed in 50% of placentas obtained from preeclamptic women (
P=
0.001). In these placentas, C4d was observed in a focal (9/14) or diffuse (5/14) staining pattern at the syncytiotrophoblast. With respect to C1q, mannose-binding lectin, and properdin, no differences were observed between cases and controls. In preeclamptic women, diffuse placental C4d was associated with a significantly lower gestational age at delivery. Furthermore, the mRNA expression of the complement regulatory proteins CD55 and CD59 was significantly upregulated in preeclampsia. In conclusion, there is evidence for increased classical pathway activation and altered complement regulation in preeclampsia. The relation between C4d and lower gestational age at birth suggests that the extent of complement dysregulation is associated with the severity of preeclampsia. Inhibiting excessive complement activation may be a promising therapeutic approach in the management of preeclampsia.
Uric Acid Reduction Rectifies Prehypertension in Obese Adolescents
Authors: Soletsky Beth , Feig Daniel I.
Published: September 2012

Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy.
cGMP-Dependent Activation of Protein Kinase G Precludes Disulfide Activation
Authors: Burgoyne Joseph Robert , Prysyazhna Oleksandra , Rudyk Olena , Eaton Philip
Published: September 2012

Protein kinase G (PKG) is activated by nitric oxide (NO)-induced cGMP binding or alternatively by oxidant-induced interprotein disulfide formation. We found preactivation with cGMP attenuated PKG oxidation. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) blockade of cGMP production increased disulfide PKG to 13±2% and 29±4% of total in aorta and mesenteries, respectively. This was potentially anomalous, because we observed 2.7-fold higher NO levels in aorta than mesenteries; consequently, we had anticipated that ODQ would induce more disulfide in the conduit vessel. ODQ also constricted aorta, whereas it had no effect on mesenteries. Thus, mesenteries, but not aorta, can compensate for loss of NO-cGMP by recruiting disulfide activation of PKG. Mechanistically, this is explained by loss of cGMP allowing disulfide formation in response to basal oxidant production. Why aorta treated with ODQ generated less PKG disulfide that is insufficient to induce vasoconstriction was unclear. One potential explanation, especially because aorta were much less sensitive than mesenteries to exogenous H
2
O
2
-induced relaxation (EC
50
=205±24 and 33±2 µmol/L, respectively) was that conduit vessels may have higher peroxidase capacity. Indeed, we found that aorta express 49±22% and 80±25% more peroxiredoxin and thioredoxin, respectively, than mesenteries, and their 2-Cys peroxiredoxin peroxidatic cysteines were also less sensitive to hyperoxidation. The higher peroxidase capacity of aortas would explain their constriction during cGMP removal and their insensitivity to H
2
O
2
-induced relaxation compared with mesenteries. In summary, cGMP binding to PKG induces a state that is resistant to disulfide formation. Consequently, cGMP depletion sensitizes PKG to oxidation; this happens to a lesser extent in aortas than in mesenteries, because the conduit vessels generate more NO and express more peroxiredoxin.
EP1 Disruption Attenuates End-Organ Damage in a Mouse Model of Hypertension
Authors: Bartlett Christina S. , Boyd Kelli L. , Harris Raymond C. , Zent Roy , Breyer Richard M.
Published: September 2012

Prostaglandin E
2
is a major prostanoid found in the kidney and vasculature contributing to the regulation of blood pressure. The prostaglandin E
2
receptor EP1 has been shown to contribute to hypertension by mediating angiotensin II-dependent vasoconstriction, although its precise role is incompletely characterized. Disruption of the EP1 receptor in C57BL/6J mice reduced the incidence of mortality during severe hypertension induced by uninephrectomy, deoxycorticosterone acetate, and angiotensin II. Mortality was dependent on all components of the model. Death was a result of aortic aneurysm rupture or occurred after development of anasarca, each of which was reduced in EP1−/− mice. Mean arterial pressure was increased in treated EP1+/+ and EP1−/− mice; however, this elevation was significantly lower in EP1−/− mice. Blood pressure reduction via administration of hydralazine phenocopied EP1−/− mice. Thus, reduction in blood pressure by disruption of EP1 reduced incidence of mortality and decreased organ damage, suggesting that EP1 receptor blockade may be a viable target for antihypertensive therapy.
Lennon and Jesus
Authors: Regev Eyal
Published: September 2012

John Lennon’s religious discourse, as manifested in his many interviews and song lyrics, is characterized by two conflicting elements: a strong interest in Jesus as a moral figure, and criticism of the Christian establishment. Lennon’s message of love and peace was inspired by certain Christian ideas that he attributed to Jesus, as well as by his recognition of the declining relevance of established religion in society. Lennon also made close connections between the Beatles and religion. His ideas on religion therefore demonstrate both individualistic religious sensibilities and motivations that run counter to the religious establishment, and even, in a sense, aim to replace it. Lennon’s attitudes toward religion are examined here in light of trends toward secularization in the 1960s; studies of religious experimentalism; and the non-conventional religious typology of humanism as a quasi-religion.
Contextualizing The Woman’s Bible
Authors: de Groot Christiana
Published: September 2012

Reading Elizabeth Cady Stanton’s The Woman’s Bible in the context of other nineteenth-century women interpreters of Scripture and in the context of her development as a thinker and activist for abolition as well as women’s rights creates a more nuanced understanding of her work. Stanton’s two-volume commentary, published in 1895 and 1898, stands in a tradition of women reflecting on women in the Bible that began eighty years earlier. Her contributions are read in dialogue with other women interpreters, noting both similarities and differences. In addition, her writings in The Woman’s Bible are contrasted with an essay on the Decalogue which she wrote in 1860 to advocate for abolition. Here she writes as a reformer, and reads the Bible from a liberationist viewpoint. Stanton’s differing reading strategies are explored in their particular historical context so that developments in her own thinking are clarified.
Comparing the Golden Rule in Hindu and Christian Religious Texts
Authors: Bakker Freek L.
Published: September 2012

This article compares the oldest Hindu versions of the Golden Rule found in the Mahabharata with those in the gospels. What may the Hindu texts, which usually receive little attention, contribute to the understanding of the New Testament renditions? Methodologically the article draws from Clooney’s Comparative Theology and Moyaert’s approach of hermeneutical hospitality. In the Hindu texts the rule is understood in terms of ahimsa (non-violence). This seems to be close to Luke’s version, in which the maxim is closely connected with the appeal to love one’s enemies. The Mahabharata, however, reveals also the maxim’s potency to use reciprocity as a strategy for making peace. So, the reciprocity stressed in Matthew is also important.