bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a New Natural Seasoning on the Formation of Pyrazines in Barbecued Beef Patties
Authors: García-Lomillo Javier , González-SanJosé Ma Luisa , Del Pino-García Raquel , Ortega-Heras Miriam , Muñiz-Rodríguez Pilar
Published: July 2016

The formation of pyrazines in food cooking is required to obtain satisfactory “roasted” flavor. The aim of this work was to evaluate the effect of a new red wine pomace seasoning (RWPS) on the formation of pyrazines in barbecued beef patties. Five pyrazines were successfully identified, 2,5-dimethylpyrazine being the most abundant. Although 2-ethyl-5-methylpyrazine was in lower levels, it presented the highest odor units, due to its low threshold. RWPS enhanced the formation of the five identified pyrazines (2.1 times), without relevant changes in the proportion between them. The highest increase was observed for 2-ethyl-6-methylpyrazine (3 times higher than in control). These results were corroborated by electronic nose analysis, presenting RWPS beef patties higher odor intensities. Mechanisms to explain these effects are also proposed in the present work, and the high content of polyphenols seems to be the major cause of the observed results. The use of RWPS could improve the flavor characteristics of meat products or enable using less intense cooking conditions with no changes in the flavor.
Role of ROS and RNS Sources in Physiological and Pathological Conditions
Authors: Di Meo Sergio , Reed Tanea T. , Venditti Paola , Victor Victor Manuel
Published: July 2016

There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis.
Soft Tissue Augmentation with Autologous Platelet Gel andβ-TCP: A Histologic and Histometric Study in Mice
Authors: Scarano Antonio , Ceccarelli Maurizio , Marchetti Massimiliano , Piattelli Adriano , Mortellaro Carmen
Published: July 2016

Background. Facial aging is a dynamic process involving both soft tissue and bony structures. Skin atrophy, with loss of tone, elasticity, and distribution of facial fat, coupled with gravity and muscle activity, leads to wrinkling and folds.Purpose. The aim of the study was to evaluate microporous tricalcium phosphate (β-TCP) and autologous platelet gel (APG) mix in mice for oral and maxillofacial soft tissue augmentation. The hypothesis was thatβ-TCP added with APG was able to increase the biostimulating effect on fibroblasts and quicken resorption.Materials and Methods. Ten female, 6–8-week-old black-haired mice were selected.β-TCP/APG gel was injected into one cheek; the other was used as control. The animals were sacrificed at 8 weeks and histologically evaluated.Results. The new fibroblast was intensively stained with acid fuchsin and presented in contact withβ-TCP. At higher magnification, actively secreting fibroblasts were observed at the periphery ofβ-TCP with a well differentiated fibroblast cell line and blood vessels. Acid fuchsin stained cutaneous structures in pink: no epidermal/dermal alterations or pathological inflammatory infiltrates were detected. The margins ofβ-TCP granules were clear and not diffused near tissues.Conclusion. APG withβ-TCP preserves skin morphology, without immune response, with an excellent tolerability and is a promising scaffold for cells and biomaterial for soft tissue augmentation.
Acute Disseminated Encephalomyelitis following Vaccination against Hepatitis B in a Child: A Case Report and Literature Review
Authors: Yuan Jun-liang , Wang Shuang-kun , Guo Xiao-juan , Hu Wen-li
Published: July 2016

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system, which has been associated with several vaccines such as rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, and the Hog vaccine. Here, we presented a case of 12-year-old child who suffered from ADEM three weeks after hepatitis B vaccination. He was admitted to our hospital with symptoms of weakness of limbs, high fever, and alteration of consciousness. Some abnormalities were also found in CSF. Treatment with high-dose corticosteroids and intravenous immunoglobulin had significant effect, with marked improvement of the clinical symptoms and the results of CSF. The findings of MRI also detected some abnormal lesions located in both brain and spinal cord. The clinical features, the findings of CSF and MRI, and therapeutic effect may contribute to such diagnosis of ADEM.
Licensed Shared Access System Possibilities for Public Safety
Authors: Lähetkangas Kalle , Saarnisaari Harri , Hulkkonen Ari
Published: July 2016

We investigate the licensed shared access (LSA) concept based spectrum sharing ideas between public safety (PS) and commercial radio systems. While the concept of LSA has been well developed, it has not been thoroughly investigated from the public safety (PS) users’ point of view, who have special requirements and also should benefit from the concept. Herein, we discuss the alternatives for spectrum sharing between PS and commercial systems. In particular, we proceed to develop robust solutions for LSA use cases where connections to the LSA system may fail. We simulate the proposed system with different failure models. The results show that the method offers reliable LSA spectrum sharing in various conditions assuming that the system parameters are set properly. The paper gives guidelines to set these parameters.
Toxic Epidermal Necrolysis-Like Lesions and Systemic Lupus Erythematosus Possibly Triggered by Sulfasalazine
Authors: Krabbe Simon , Gül Cigdem , Andersen Bjarne , Tvede Niels
Published: July 2016

This case report describes a patient with arthritis of the large joints, bilateral sacroiliitis, and positive anti-SSA and anti-dsDNA antibody, who received sulfasalazine and shortly thereafter became critically ill. He developed toxic epidermal necrolysis, hemolytic anemia, lymphopenia, markedly elevated ferritin, and muscle wasting. A diagnosis of systemic lupus erythematosus was made, and mycophenolate mofetil and systemic glucocorticoids brought this severe disease under control. Toxic epidermal necrolysis-like lesions and hemophagocytic syndrome have been reported as manifestations of systemic lupus erythematosus. This patient possibly had spondyloarthritis or an undifferentiated connective tissue disease at presentation, and we suggest, based on the timing of events, that sulfasalazine may have acted as a trigger of the severe disease manifestations.
α‐Mangostin Induces Apoptosis and Cell Cycle Arrest in Oral Squamous Cell Carcinoma Cell
Authors: Kwak Hyun-Ho , Kim In-Ryoung , Kim Hye-Jin , Park Bong-Soo , Yu Su-Bin
Published: July 2016

Mangosteen has long been used as a traditional medicine and is known to have antibacterial, antioxidant, and anticancer effects. Although the effects of α‐mangostin, a natural compound extracted from the pericarp of mangosteen, have been investigated in many studies, there is limited data on the effects of the compound in human oral squamous cell carcinoma (OSCC). In this study, α‐mangostin was assessed as a potential anticancer agent against human OSCC cells. α‐Mangostin inhibited cell proliferation and induced cell death in OSCC cells in a dose‐ and time‐dependent manner with little to no effect on normal human PDLF cells. α‐Mangostin treatment clearly showed apoptotic evidences such as nuclear fragmentation and accumulation of annexin V and PI‐positive cells on OSCC cells. α‐Mangostin treatment also caused the collapse of mitochondrial membrane potential and the translocation of cytochrome c from the mitochondria into the cytosol. The expressions of the mitochondria‐related proteins were activated by α‐mangostin. Treatment with α‐mangostin also induced G1 phase arrest and downregulated cell cycle‐related proteins (CDK/cyclin). Hence, α‐mangostin specifically induces cell death and inhibits proliferation in OSCC cells via the intrinsic apoptosis pathway and cell cycle arrest at the G1 phase, suggesting that α‐mangostin may be an effective agent for the treatment of OSCC.
Cerebral Blood Flow, Heart Rate, and Blood Pressure Patterns during the Tilt Test in Common Orthostatic Syndromes
Authors: Novak Peter
Published: July 2016

Objective. The head-up tilt test is widely used for evaluation of orthostatic intolerance. Although orthostatic symptoms usually reflect cerebral hypoperfusion, the cerebral blood flow velocity (CBFv) profile in orthostatic syndromes is not well described. This study evaluated CBFv and cardiovascular patterns associated with the tilt test in common orthostatic syndromes. Methods. This retrospective study analyzed the tilt test of patients with history of orthostatic intolerance. The following signals were recorded: ECG, blood pressure, CBFv using transcranial Doppler, respiratory signals, and end tidal CO2. Results. Data from 744 patients were analyzed. Characteristic pattern associated with a particular orthostatic syndrome can be grouped into abnormalities predominantly affecting blood pressure (orthostatic hypotension, orthostatic hypertension syndrome, vasomotor oscillations, and neurally mediated syncope—cardioinhibitory, vasodepressor, and mixed), cerebral blood flow (orthostatic hypoperfusion syndrome, primary cerebral autoregulatory failure), and heart rate (tachycardia syndromes: postural tachycardia syndrome, paroxysmal sinus tachycardia, and inappropriate sinus tachycardia). Psychogenic pseudosyncope is associated with stable CBFv. Conclusions. The tilt test is useful add-on in diagnosis of several orthostatic syndromes. However diagnostic criteria for several syndromes had to be modified to allow unambiguous pattern classification. CBFv monitoring in addition to blood pressure and heart rate may increase diagnostic yield of the tilt test.
Exposure to Music Alters Cell Viability and Cell Motility of Human Nonauditory Cells in Culture
Authors: Lestard Nathalia R. , Capella Marcia A. M.
Published: July 2016

Although music is part of virtually all cultures in the world, little is known about how it affects us. Since the beginning of this century several studies suggested that the response to music, and to sound in general, is complex and might not be exclusively due to emotion, given that cell types other than auditory hair cells can also directly react to audible sound. The present study was designed to better understand the direct effects of acoustic vibrations, in the form of music, in human cells in culture. Our results suggest that the mechanisms of cell growth arrest and/or cell death induced by acoustic vibrations are similar for auditory and nonauditory cells.
Comparative Analysis of the Effectiveness of Regulation of Aeration Depending on the Quantitative Characteristics of Treated Sewage Water
Authors: Malovanyy Myroslav , Shandrovych Vira , Malovanyy Andriy , Polyuzhyn Igor
Published: July 2016

Monitoring of work of the aeration tanks of operating town treatment plants is done. Based on the obtained results a conclusion has been drawn that sewage water is improperly treated from ammonium nitrogen. The velocity of the aeration process, depending on the concentration of dissolved oxygen and ammonium nitrogen, is investigated. The obtained investigation data became the basis for modeling the aeration process in industrial conditions depending on the required initial concentration of ammonium nitrogen.
Does Hsp60 Provide a Link between Mitochondrial Stress and Inflammation in Diabetes Mellitus?
Authors: Juwono Joshua , Martinus Ryan D.
Published: July 2016

The focus of this review is to summarise the known relationships between the expression of heat shock protein 60 (Hsp60) and its association with the pathogenesis of Type 1 and Type 2 diabetes mellitus. Hsp60 is a mitochondrial stress protein that is induced by mitochondrial impairment. It is known to be secreted from a number of cell types and circulating levels have been documented in both Types 1 and 2 diabetes mellitus patients. The biological significance of extracellular Hsp60, however, remains to be established. We will examine the links between Hsp60 and cellular anti- and proinflammatory processes and specifically address how Hsp60 appears to affect immune inflammation by at least two different mechanisms: as a ligand for innate immune receptors and as an antigen recognised by adaptive immune receptors. We will also look at the role of Hsp60 during immune cell activation in atherosclerosis, a significant risk factor during the pathogenesis of diabetes mellitus.
Overcapacity as a Barrier to Renewable Energy Deployment: The Spanish Case
Authors: del Río Pablo , Janeiro Luis
Published: July 2016

Renewable energy sources (RES) play a critical role in the low-carbon energy transition. Although there is quite an abundant literature on the barriers to RES, the analysis of the electricity generation overcapacity as a barrier to further RES penetration has received scant attention. This paper tries to cover this gap. Its aim is to analyse the causes and consequences of overcapacity, with a special focus on the impact on RES deployment, using Spain as a case study. It also analyses the policies which may mitigate this problem in both the short and the longer terms.
Fractional-Order Discrete-Time Laguerre Filters: A New Tool for Modeling and Stability Analysis of Fractional-Order LTI SISO Systems
Authors: Stanisławski Rafał , Latawiec Krzysztof J.
Published: July 2016

This paper presents new results on modeling and analysis of dynamics of fractional-order discrete-time linear time-invariant single-input single-output (LTI SISO) systems by means of new, two-layer, “fractional-order discrete-time Laguerre filters.” It is interesting that the fractionality of the filters at the upper system dynamics layer is directly projected from the lower Laguerre-based approximation layer for the Grünwald-Letnikov difference. A new stability criterion for discrete-time fractional-order Laguerre-based LTI SISO systems is introduced and supplemented with a stability preservation analysis. Both the stability criterion and the stability preservation analysis bring up rather surprising results, which is illustrated with simulation examples.
miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer
Authors: D'Ippolito Elvira , Plantamura Ilaria , Bongiovanni Lucia , Casalini Patrizia , Baroni Sara , Piovan Claudia , Orlandi Rosaria , Gualeni Ambra V. , Gloghini Annunziata , Rossini Anna , Cresta Sara , Tessari Anna , De Braud Filippo , Di Leva Gianpiero , Tripodo Claudio , Iorio Marilena V.
Published: July 2016

Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFRβ-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro. Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231–stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. Cancer Res; 76(18); 5562–72. ©2016 AACR.
Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers
Authors: Facchinetti Francesco , Loriot Yohann , Kuo Mei-Shiue , Mahjoubi Linda , Lacroix Ludovic , Planchard David , Besse Benjamin , Farace Françoise , Auger Nathalie , Remon Jordi , Scoazec Jean-Yves , André Fabrice , Soria Jean-Charles , Friboulet Luc
Published: July 2016

Background: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non–small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.

Methods: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)–ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.

Results: Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.

Conclusions: Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983–91. ©2016 AACR.
Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance
Authors:   The Cancer Target Discovery and Development Network
Published: July 2016

The Cancer Target Discovery and Development (CTD2) Network was established to accelerate the transformation of “Big Data” into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and biomarker strategies for cancer. Mol Cancer Res; 14(8); 675–82. ©2016 AACR.
Colorectal Cancer with BRAF D594G Mutation Is Not Associated with Microsatellite Instability or Poor Prognosis
Authors: Amaki-Takao Misato , Yamaguchi Tatsuro , Natsume Soichiro , Iijima Takeru , Wakaume Rika , Takahashi Keiichi , Matsumoto Hiroshi , Miyaki Michiko
Published: July 2016

Objective:BRAF D594G mutations in colorectal cancer patients are not clearly understood. We retrospectively investigated the clinicopathological features of colorectal cancers with BRAF D594G mutations. Methods: We selected 908 colorectal cancer patients who underwent surgical resection from January 2008 to January 2013, and assessed BRAF, KRAS, microsatellite instability, and CpG island methylator phenotype (CIMP). Results: We detected BRAF D594G in 7 patients and BRAF V600E in 45 patients. The clinicopathological features of cancers with BRAF D594G mutation were similar to those with BRAF wild-type, but differed from those with BRAF V600E mutations. Regarding microsatellite instability status, 44.4% of cases with BRAF V600E mutations exhibited high microsatellite instability, compared to 14.3% of those with BRAF D594G mutations and 4.4% of those with BRAF wild-type. There were no CIMP-positive tumors in cancers with BRAF D594G mutations, whereas 67.8% of tumors with BRAF V600E mutations were CIMP-positive. In stage IV cancers, the survival rates of patients at 2 years were 8.5, 50.0, and 68.2% in the BRAF V600E mutation, BRAF D594G mutation, and BRAF wild-type groups, respectively. Conclusion: Colorectal cancers with BRAF D594G mutations exhibit similar clinicopathological features, microsatellite instability status, and prognosis as those with BRAF wild-type.
Clinicopathological Characteristics, Surgery and Survival Outcomes of Patients with Duodenal Gastrointestinal Stromal Tumors
Authors: Sugase Takahito , Takahashi Tsuyoshi , Nakajima Kiyokazu , Hirota Seiichi , Masuzawa Toru , Nishida Toshirou , Kimura Yutaka , Miyazaki Yasuhiro , Makino Tomoki , Kurokawa Yukinori , Yamasaki Makoto , Takiguchi Shuji , Mori Masaki , Doki Yuichiro
Published: July 2016

Background: Duodenal gastrointestinal stromal tumors (GISTs) are a rare subset of GISTs (3-5%), and their clinicopathological features have not been fully described. The purpose of this retrospective study was to examine these characteristics and compare the operative procedures. Methods: Twenty-five patients with duodenal GIST underwent complete resection, local resection (LR) or pancreaticoduodenectomy (PD) from 1990 to 2014 at our 2 hospitals. We analyzed patient characteristics, treatments, histological examinations, postoperative complications and survival outcomes. Results: Twelve patients (48%) with no symptoms were incidentally diagnosed for unrelated reasons. Sixteen patients (64%) had c-kit mutations while 6 (24%) were wild-type, including 4 with a history of neurofibromatosis type 1. Comparing LR (n = 16) and PD (n = 9), the recurrence-free survival rate was significantly worse for PD. On multivariate analysis, however, tumor size was an independent and significant prognostic factor, but not operative procedure. There was no body weight change with LR, but body weight decreased by 7% with PD. Conclusion: Duodenal GISTs had different characteristic genetic mutations compared to other GISTs. LR for duodenal GISTs appears to be oncologically and nutritionally feasible.
Resting Energy Expenditure of Black Overweight Women in South Africa Is Lower than of White Women
Authors: Olivier Natascha , Wenhold Friedeburg A.M. , Becker Piet
Published: July 2016

Background: Overweight affects 65% of black South African women. Effective weight management requires accurate measurement or estimation of energy expenditure. Aims: The study aimed to determine, among overweight women, whether measured resting energy expenditure (REE) differs between black and white participants, and the performance of REE estimation equations. Methods: The REE of 44 black (age 39.6 ± 9.7 years, body mass index (BMI) 35.1 ± 6.2 kg/m2) and 41 white (age 38.0 ± 11.6 years, BMI 33.9 ± 7.6 kg/m2) women was measured with indirect calorimetry and estimated with equations. Body composition was assessed with multi-frequency bioelectrical impedance analysis. Differences in REE were determined with t tests (Welch), and included adjustment for fat free mass (FFM) and BMI, and for FFM index (FFMI). Results: Measured REE was 585 kJ/day (95% CI 264-905; p = 0.0005) and 861 kJ/day (95% CI 499-1,221; p < 0.0001) lower in black than in white women when adjusted for FFM and BMI, and FFMI, respectively. Out of 14 equations, 13 underestimated REE (error range 2,261 ± 727 kJ/day (Bernstein equation, white women) to 8 ± 782 kJ/day (BMI equation, black women)). Conclusions: Black overweight women have significantly lower REE than their white counterparts. No tested estimation equation provided satisfactory results across race/ethnicity. REE measurements or development of overweight- or race/ethnicity-specific estimation equations are recommended.
Determinants of Physical Activity in Patients with Chronic Obstructive Pulmonary Disease: A 5-Year Prospective Follow-Up Study
Authors: Yu Tsung , Frei Anja , ter Riet Gerben , Puhan Milo A.
Published: July 2016

Background: Although many studies examined determinants of physical activity in patients with chronic obstructive pulmonary disease (COPD), most were cross-sectional and focused on single determinants only. Objectives: The aim of this study was to determine how COPD patients' physical activity changes over time and to identify the determinants of physical activity using multivariable and longitudinal methods. Methods: In a prospective cohort study, 409 primary care patients with COPD in the Netherlands and Switzerland were followed for up to 5 years. Physical activity was assessed at baseline and every 6 months using the Longitudinal Aging Study Amsterdam Physical Activity Questionnaire (LAPAQ) adapted to a 0- to 23-point scale. We studied the associations between determinants at baseline and patients' long-term physical activity levels using linear mixed models. Results: Unadjusted analysis showed an overall gradual decline in physical activity (0.22 points of the LAPAQ scale every 6 months, 95% CI: 0.17-0.28; p < 0.001). In multivariable analyses, baseline determinants that were independently associated (p ≤ 0.05) with lower long-term physical activity levels included (starting from coefficients with the smallest p value) lower exercise capacity, older age, working, more smoking pack-years, more fatigued, male sex, lower educational levels, previously not in fitness programs, more depressed, lower lung function, lower overall health status, and more prescription drug use. Conclusions: We found that physical activity of COPD patients may decline more than reported in the healthy elderly. Longitudinal analysis identified independent determinants of physical activity, which allows the identification of patients having low physical activity levels and who may benefit from physical activity interventions.
Drugs That May Cause or Exacerbate Heart Failure
Authors: Page Robert L. , O’Bryant Cindy L. , Cheng Davy , Dow Tristan J. , Ky Bonnie , Stein C. Michael , Spencer Anne P. , Trupp Robin J. , Lindenfeld JoAnn
Published: July 2016

Heart failure is a common, costly, and debilitating syndrome that is associated with a highly complex drug regimen, a large number of comorbidities, and a large and often disparate number of healthcare providers. All of these factors conspire to increase the risk of heart failure exacerbation by direct myocardial toxicity, drug-drug interactions, or both. This scientific statement is designed to serve as a comprehensive and accessible source of drugs that may cause or exacerbate heart failure to assist healthcare providers in improving the quality of care for these patients.
Left Atrial Appendage Electrical Isolation and Concomitant Device Occlusion to Treat Persistent Atrial Fibrillation
Authors: Panikker Sandeep , Jarman Julian W.E. , Virmani Renu , Kutys Robert , Haldar Shouvik , Lim Eric , Butcher Charles , Khan Habib , Mantziari Lilian , Nicol Edward , Foran John P. , Markides Vias , Wong Tom
Published: July 2016

Background—

Left atrial appendage (LAA) electric isolation is reported to improve persistent atrial fibrillation (AF) ablation outcomes. However, loss of LAA mechanical function may increase thromboembolic risk. Concomitant LAA electric isolation and occlusion as part of conventional AF ablation has never been tested in humans. We therefore evaluated the feasibility, safety, and efficacy of LAA electric isolation and occlusion in patients undergoing long-standing persistent AF ablation.

Methods and Results—

Patients with long-standing persistent AF (age, 68±7 years; left atrium diameter, 46±3 mm; and AF duration, 25±15 months) underwent AF ablation, LAA electric isolation, and occlusion. Outcomes were compared with a balanced (1:2 ratio) control group who had AF ablation alone. Among 22 patients who underwent ablation, LAA electric isolation was possible in 20. Intraprocedural LAA reconnection occurred in 17 of 20 (85%) patients, predominantly at anterior and superior locations. All were reisolated. LAA occlusion was successful in all 20 patients. There were no major periprocedural complications. Imaging at 45 days and 9 months confirmed satisfactory device position and excluded pericardial effusion. One of twenty (5%) patients had a gap of ≥5 mm requiring anticoagulation. Nineteen of twenty (95%) patients stopped warfarin at 3 months. Without antiarrhythmic drugs, freedom from AF at 12 months after a single procedure was significantly higher in the study group (19/20, 95%) than in the control group (25/40, 63%),
P
=0.036. Freedom from atrial arrhythmias was demonstrated in 12 of 20 (60%) and 18 of 20 (90%) patients after 1 and ≤2 procedures (mean, 1.3), respectively.

Conclusions—

Persistent AF ablation, LAA electric isolation, and mechanical occlusion can be performed concomitantly. This technique may improve the success of persistent AF ablation while obviating the need for chronic anticoagulation.

Clinical Trial Registration—

URL:
https://clinicaltrials.gov
. Unique identifier: NCT02028130.
Identification of Concealed and Manifest Long QT Syndrome Using a Novel T Wave Analysis Program
Authors: Sugrue Alan , Noseworthy Peter A. , Kremen Vaclav , Bos J. Martijn , Qiang Bo , Rohatgi Ram K. , Sapir Yehu , Attia Zachi I. , Brady Peter , Asirvatham Samuel J. , Friedman Paul A. , Ackerman Michael J.
Published: July 2016

Background—

Congenital long QT syndrome (LQTS) is characterized by QT prolongation. However, the QT interval itself is insufficient for diagnosis, unless the corrected QT interval is repeatedly ≥500 ms without an acquired explanation. Further, the majority of LQTS patients have a corrected QT interval below this threshold, and a significant minority has normal resting corrected QT interval values. Here, we aimed to develop and validate a novel, quantitative T wave morphological analysis program to differentiate LQTS patients from healthy controls.

Methods and Results—

We analyzed a genotyped cohort of 420 patients (22±16 years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using a novel, proprietary T wave analysis program that quantitates subtle changes in T wave morphology. The top 3 discriminating features in each ECG lead were determined and the lead with the best discrimination selected. Classification was performed using a linear discriminant classifier and validated on an untouched cohort. The top 3 features were Tpeak–Tend interval, T wave left slope, and T wave center of gravity
x
axis (last 25% of the T wave). Lead V6 had the best discrimination. It could distinguish 86.8% of LQTS patients from healthy controls. Moreover, it distinguished 83.33% of patients with concealed LQTS from controls, despite having essentially identical resting corrected QT interval values.

Conclusions—

T wave quantitative analysis on the 12-lead surface ECG provides an effective, novel tool to distinguish patients with either LQT1/LQT2 from healthy matched controls. It can provide guidance while mutation-specific genetic testing is in motion for family members.
Retrograde Coronary Venous Ethanol Infusion for Ablation of Refractory Ventricular Tachycardia
Authors: Kreidieh Bahij , Rodríguez-Mañero Moisés , A. Schurmann Paul , Ibarra-Cortez Sergio Hugo , Dave Amish S. , Valderrábano Miguel
Published: July 2016

Background—

Radiofrequency ablation (RFA) of ventricular tachycardia (VT) can fail because of inaccessibility to the VT substrate. Transarterial coronary ethanol ablation can be effective but entails arterial instrumentation risk. We hypothesized that retrograde coronary venous ethanol ablation can be an alternative bail-out approach to failed VT RFA.

Methods and Results—

Out of 334 consecutive patients undergoing VT/premature ventricular contraction ablation, 7 patients underwent retrograde coronary venous ethanol ablation. Six out of 7 patients had failed RFA attempts (including epicardial in 3). Coronary venogram-guided venous mapping was performed using a 4F quadripolar catheter or an alligator-clip–connected angioplasty wire. Targeted veins included those with early presystolic potentials and pace-maps matching VT/premature ventricular contraction. An angioplasty balloon (1.5–2×6 mm) was used to deliver 1 to 4 cc of 98% ethanol into a septal branch of the anterior interventricular vein in 5 patients with left ventricular summit VT, a septal branch of the middle cardiac vein, and a posterolateral coronary vein (n=1 each). The clinical VT was successfully ablated acutely in all patients. There were no complications of retrograde coronary venous ethanol ablation, but 1 patient developed pericardial and pleural effusion attributed to pericardial instrumentation. On follow-up of 590±722 days, VT recurred in 4 out of 7 patients, 3 of whom were successfully reablated with RFA.

Conclusions—

Retrograde coronary venous ethanol ablation is safe and feasible as a bail-out approach to failed VT RFA, particularly those originating from the left ventricular summit.
Prevalence, Features, and Prognostic Importance of Edge Dissection After Drug-Eluting Stent Implantation
Authors: Kobayashi Nobuaki , Mintz Gary S. , Witzenbichler Bernhard , Metzger D. Christopher , Rinaldi Michael J. , Duffy Peter L. , Weisz Giora , Stuckey Thomas D. , Brodie Bruce R. , Parvataneni Rupa , Kirtane Ajay J. , Stone Gregg W. , Maehara Akiko
Published: July 2016

Background—

Intravascular ultrasound detects stent edge dissections after percutaneous coronary intervention that are not seen angiographically. This study investigated the association between stent edge dissections and clinical outcomes.

Methods and Results—

ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) was a large-scale, prospective, multicenter study of patients undergoing drug-eluting stent implantation. In this prospective substudy, 2062 patients (2433 lesions) were evaluated with intravascular ultrasound to characterize the morphological features and clinical outcomes of stent edge dissection after percutaneous coronary intervention. The prevalence of post–percutaneous coronary intervention stent edge dissection was 6.6% per lesion (161 of 2433). Calcified plaque at the proximal stent edge (relative risk [RR]=1.72;
P
=0.04) and proximal stent edge expansion (RR=1.18;
P
=0.004) were predictors for proximal dissection; attenuated plaque at the distal stent edge (RR=3.52;
P
=0.004), distal reference plaque burden (RR=1.56;
P
<0.0001), and distal edge stent expansion (RR=1.11;
P
=0.02) were predictors for distal dissection. At 1-year follow-up, target lesion revascularization was more common in lesions with versus without dissection (5.2% versus 2.7%;
P
=0.04). Multivariable analysis indicated that residual dissection was associated with target lesion revascularization at 1-year follow-up (RR=2.67;
P
=0.02). Among lesions with dissection, smaller effective lumen area increased the risk of target lesion revascularization at 1-year follow-up (cutoff value of 5.1 mm
2
;
P
=0.05).

Conclusions—

Greater stent expansion and the presence of large, calcified, and/or attenuated plaques were independent predictors of stent edge dissection. Residual stent edge dissection, especially with a smaller effective lumen area, was associated with target lesion revascularization during 1-year follow-up after drug-eluting stent implantation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00638794.
NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart
Authors: Matsuda Takahisa , Zhai Peiyong , Sciarretta Sebastiano , Zhang Yu , Jeong Jae Im , Ikeda Shohei , Park Jiyeon , Hsu Chiao-Po , Tian Bin , Pan Duojia , Sadoshima Junichi , Del Re Dominic P.
Published: July 2016

Rationale:

NF2 (neurofibromin 2) is an established tumor suppressor that promotes apoptosis and inhibits growth in a variety of cell types, yet its function in cardiomyocytes remains largely unknown.

Objective:

We sought to determine the role of NF2 in cardiomyocyte apoptosis and ischemia/reperfusion (I/R) injury in the heart.

Methods and Results:

We investigated the function of NF2 in isolated cardiomyocytes and mouse myocardium at baseline and in response to oxidative stress. NF2 was activated in cardiomyocytes subjected to H
2
O
2
and in murine hearts subjected to I/R. Increased NF2 expression promoted the activation of Mst1 (mammalian sterile 20–like kinase 1) and the inhibition of Yap (Yes-associated protein), whereas knockdown of NF2 attenuated these responses after oxidative stress. NF2 increased the apoptosis of cardiomyocytes that appeared dependent on Mst1 activity. Mice deficient for NF2 in cardiomyocytes,
NF2
cardiomyocyte-specific knockout (CKO), were protected against global I/R ex vivo and showed improved cardiac functional recovery. Moreover,
NF2
cardiomyocyte-specific knockout mice were protected against I/R injury in vivo and showed the upregulation of Yap target gene expression. Mechanistically, we observed nuclear association between NF2 and its activator MYPT-1 (myosin phosphatase target subunit 1) in cardiomyocytes, and a subpopulation of stress-induced nuclear Mst1 was diminished in
NF2
CKO hearts. Finally, mice deficient for both NF2 and Yap failed to show protection against I/R indicating that Yap is an important target of NF2 in the adult heart.

Conclusions:

NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through the activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.
Bioresorbable Vascular Scaffolds for Coronary Revascularization
Authors: Kereiakes Dean J. , Onuma Yoshinobu , Serruys Patrick W. , Stone Gregg W.
Published: July 2016

Contemporary metallic drug-eluting stents are associated with very good 1-year outcomes but an ongoing risk of stent-related adverse events (thrombosis, myocardial infarction, restenosis) after 1 year. The pathogenesis of these very late events is likely related to the permanent presence of the metal stent frame or polymer. Bioresorbable scaffolds have been developed to provide drug delivery and mechanical support functions similar to metallic drug-eluting stents, followed by complete resorption with recovery of more normal vascular structure and function, potentially improving very late clinical outcomes. A first-generation bioresorbable scaffold has been demonstrated to be noninferior to a contemporary metallic drug-eluting stents for overall 1-year patient-oriented and device-oriented outcomes. Increased rates of scaffold thrombosis and target vessel-related myocardial infarction were noted that may be mitigated by improved patient and lesion selection, procedural technique, and device iteration. Large-scale, randomized, clinical trials are ongoing to determine the long-term relative efficacy and safety of bioresorbable scaffolds compared with current metallic drug-eluting stents.
One-Year Clinical Outcomes With SAPIEN 3 Transcatheter Aortic Valve Replacement in High-Risk and Inoperable Patients With Severe Aortic Stenosis
Authors: Herrmann Howard C. , Thourani Vinod H. , Kodali Susheel K. , Makkar Raj R. , Szeto Wilson Y. , Anwaruddin Saif , Desai Nimesh , Lim Scott , Malaisrie S. Chris , Kereiakes Dean J. , Ramee Steven , Greason Kevin L. , Kapadia Samir , Babaliaros Vasilis , Hahn Rebecca T. , Pibarot Philippe , Weissman Neil J. , Leipsic Jonathon , Whisenant Brian K. , Webb John G. , Mack Michael J. , Leon Martin B.
Published: July 2016

Background:

In the initial PARTNER trial (Placement of Aortic Transcatheter Valves) of transcatheter aortic valve replacement for high-risk (HR) and inoperable patients, mortality at 1 year was 24% in HR and 31% in inoperable patients. A recent report of the 30-day outcomes with the low-profile SAPIEN 3 transcatheter aortic valve replacement system demonstrated very low rates of adverse events, but little is known about the longer-term outcomes with this device.

Methods:

Between October 2013 and September 2014, 583 HR (65%) or inoperable (35%) patients were treated via the transfemoral (84%) or transapical/transaortic (16%) access route at 29 US sites. Major clinical events at 1 year were adjudicated by an independent clinical events committee, and echocardiographic results were analyzed by a core laboratory.

Results:

Baseline characteristics included age of 83 years, 42% female, and median Society of Thoracic Surgeons score of 8.4%. At the 1-year follow-up, survival (all-cause) was 85.6% for all patients, 87.3% in the HR subgroup, and 82.3% in the inoperable subgroup. Survival free of all-cause and cardiovascular mortality in the transfemoral patients from the HR cohort was 87.7% and 93.3%, respectively. There was no severe paravalvular leak. Moderate paravalvular leak (2.7%) was associated with an increase in mortality at 1 year, whereas mild paravalvular leak had no significant association with mortality. Symptomatic improvement as assessed by the percentage of patients in New York Heart Association class III and IV (90.1% to 7.7% at 1 year;
P
<0.0001) and by Kansas City Cardiomyopathy Questionnaire overall summary score (improved from 46.9 to 72.4;
P
<0.0001) was marked. Multivariable predictors of 1-year mortality included alternative access, Society of Thoracic Surgeons score, and disabling stroke.

Conclusions:

In this large, adjudicated registry of SAPIEN 3 HR and inoperable patients, the very low rates of important complications resulted in a strikingly low mortality rate at 1 year. Between 30 and 365 days, the incidence of moderate paravalvular aortic regurgitation did not increase, and no association between mild paravalvular leak and 1-year mortality was observed, although a small increase in disabling stroke occurred. These results, which likely reflect device iteration and procedural evolution, support the use of transcatheter aortic valve replacement as the preferred therapy in HR and inoperable patients with aortic stenosis.

Clinical Trial Registration

: URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01314313.
Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy
Authors: Kechele Daniel O. , Dunworth William P. , Trincot Claire E. , Wetzel-Strong Sarah E. , Li Manyu , Ma Hong , Liu Jiandong , Caron Kathleen M.
Published: July 2016

RAMPs (receptor activity–modifying proteins) serve as oligomeric modulators for numerous G-protein–coupled receptors, yet elucidating the physiological relevance of these interactions remains complex.
Ramp2
null mice are embryonic lethal, with cardiovascular developmental defects similar to those observed in mice null for canonical adrenomedullin/calcitonin receptor-like receptor signaling. We aimed to genetically rescue the
Ramp2
−/−
lethality in order to further delineate the spatiotemporal requirements for RAMP2 function during development and thereby enable the elucidation of an expanded repertoire of RAMP2 functions with family B G-protein–coupled receptors in adult homeostasis. Endothelial-specific expression of
Ramp2
under the VE-cadherin promoter resulted in the partial rescue of
Ramp2
−/−
mice, demonstrating that endothelial expression of
Ramp2
is necessary and sufficient for survival. The surviving
Ramp2
−/−
Tg
animals lived to adulthood and developed spontaneous hypotension and dilated cardiomyopathy, which was not observed in adult mice lacking calcitonin receptor-like receptor. Yet, the hearts of
Ramp2
−/−
Tg
animals displayed dysregulation of family B G-protein–coupled receptors, including parathyroid hormone and glucagon receptors, as well as their downstream signaling pathways. These data suggest a functional requirement for RAMP2 in the modulation of additional G-protein–coupled receptor pathways in vivo, which is critical for sustained cardiovascular homeostasis. The cardiovascular importance of RAMP2 extends beyond the endothelium and canonical adrenomedullin/calcitonin receptor-like receptor signaling, in which future studies could elucidate novel and pharmacologically tractable pathways for treating cardiovascular diseases.
Invasively Measured Aortic Systolic Blood Pressure and Office Systolic Blood Pressure in Cardiovascular Risk Assessment
Authors: Laugesen Esben , Knudsen Søren T. , Hansen Klavs W. , Rossen Niklas B. , Jensen Lisette Okkels , Hansen Michael G. , Munkholm Henrik , Thomsen Kristian K. , Søndergaard Hanne , Bøttcher Morten , Raungaard Bent , Madsen Morten , Hulman Adam , Witte Daniel , Bøtker Hans Erik , Poulsen Per L.
Published: July 2016

Aortic systolic blood pressure (BP) represents the hemodynamic cardiac and cerebral burden more directly than office systolic BP. Whether invasively measured aortic systolic BP confers additional prognostic value beyond office BP remains debated. In this study, office systolic BP and invasively measured aortic systolic BP were recorded in 21 908 patients (mean age: 63 years; 58% men; 14% with diabetes mellitus) with stable angina pectoris undergoing elective coronary angiography during January 2001 to December 2012. Multivariate Cox models were used to assess the association with incident myocardial infarction, stroke, and death. Discrimination and reclassification were assessed using Harrell’s C and the Continuous Net Reclassification Index. Data were analyzed with and without stratification by diabetes mellitus status. During a median follow-up period of 3.7 years (range: 0.1–10.8 years), 422 strokes, 511 myocardial infarctions, and 1530 deaths occurred. Both office and aortic systolic BP were associated with stroke in patients with diabetes mellitus (hazard ratio per 10 mm Hg, 1.18 [95% confidence interval, 1.07–1.30] and 1.14 [95% confidence interval, 1.05–1.24], respectively) and with myocardial infarction in patients without diabetes mellitus (hazard ratio, 1.07 [95% confidence interval, 1.02–1.12] and 1.05 [95% confidence interval, 1.01–1.10], respectively). In models including both BP measurements, aortic BP lost statistical significance and aortic BP did not confer improvement in either C-statistics or net reclassification analysis. In conclusion, invasively measured aortic systolic BP does not add prognostic information about cardiovascular outcomes and all-cause mortality compared with office BP in patients with stable angina pectoris, either with or without diabetes mellitus.