bluuebunny/crossref_metadata_2025 huggingface dataset:
Combinations of physical activity, sedentary behaviour and sleep: relationships with health indicators in school-aged children and youth
Authors: Saunders Travis John , Gray Casey Ellen , Poitras Veronica Joan , Chaput Jean-Philippe , Janssen Ian , Katzmarzyk Peter T. , Olds Timothy , Connor Gorber Sarah , Kho Michelle E. , Sampson Margaret , Tremblay Mark S. , Carson Valerie
Published: June 2016

The purpose of this systematic review was to determine how combinations of physical activity (PA), sedentary behaviour (SB), and sleep were associated with important health indicators in children and youth aged 5–17 years. Online databases (MEDLINE, EMBASE, SPORTdiscus, CINAHL, and PsycINFO) were searched for relevant studies examining the relationship between time spent engaging in different combinations of PA, SB, and sleep with the following health indicators: adiposity, cardiometabolic biomarkers, physical fitness, emotional regulation/psychological distress, behavioural conduct/pro-social behaviour, cognition, quality of life/well-being, injuries, bone density, motor skill development, and self-esteem. PA had to be objectively measured, while sleep and SB could be objectively or subjectively measured. The quality of research evidence and risk of bias for each health indicator and for each individual study was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. A total of 13 cross-sectional studies and a single prospective cohort study reporting data from 36 560 individual participants met the inclusion criteria. Children and youth with a combination of high PA/high sleep/low SB had more desirable measures of adiposity and cardiometabolic health compared with those with a combination of low PA/low sleep/high SB. Health benefits were also observed for those with a combination of high PA/high sleep (cardiometabolic health and adiposity) or high PA/low SB (cardiometabolic health, adiposity and fitness), compared with low PA/low sleep or low PA/high SB. Of the 3 movement behaviours, PA (especially moderate- to vigorous-intensity PA) was most consistently associated with desirable health indicators. Given the lack of randomized trials, the overall quality of the available evidence was low.
Systematic review of sedentary behaviour and health indicators in school-aged children and youth: an update
Authors: Carson Valerie , Hunter Stephen , Kuzik Nicholas , Gray Casey E. , Poitras Veronica J. , Chaput Jean-Philippe , Saunders Travis J. , Katzmarzyk Peter T. , Okely Anthony D. , Connor Gorber Sarah , Kho Michelle E. , Sampson Margaret , Lee Helena , Tremblay Mark S.
Published: June 2016

This systematic review is an update examining the relationships between objectively and subjectively measured sedentary behaviour and health indicators in children and youth aged 5–17 years. EMBASE, PsycINFO, and Medline were searched in December 2014, and date limits were imposed (≥February 2010). Included studies were peer-reviewed and met the a priori-determined population (apparently healthy children and youth, mean age: 5–17 years), intervention (durations, patterns, and types of sedentary behaviours), comparator (various durations, patterns, and types of sedentary behaviours), and outcome (critical: body composition, metabolic syndrome/cardiovascular disease risk factors, behavioural conduct/pro-social behaviour, academic achievement; important: fitness, self-esteem) study criteria. Quality of evidence by outcome was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. Due to heterogeneity, a narrative analysis was conducted. A total of 235 studies (194 unique samples) were included representing 1 657 064 unique participants from 71 different countries. Higher durations/frequencies of screen time and television (TV) viewing were associated with unfavourable body composition. Higher duration/frequency of TV viewing was also associated with higher clustered cardiometabolic risk scores. Higher durations of TV viewing and video game use were associated with unfavourable behavioural conduct/pro-social behaviour. Higher durations of reading and doing homework were associated with higher academic achievement. Higher duration of screen time was associated with lower fitness. Higher durations of screen time and computer use were associated with lower self-esteem. Evidence ranged from “very low” to “moderate” quality. Higher quality studies using reliable and valid sedentary behaviour measures should confirm this largely observational evidence.
Revised distribution of an Alaskan endemic, the Alaska Hare (Lepus othus), with implications for taxonomy, biogeography, and climate change
Authors: Cason Michelle M. , Baltensperger Andrew P. , Booms Travis L. , Burns John J. , Olson Link E.
Published: June 2016

The Alaska Hare (Lepus othus Merriam 1900) is the largest lagomorph in North America but remains one of the most poorly studied terrestrial mammals on the continent. Its current distribution is restricted to western Alaska south of the Brooks Range, but historical accounts from north of the Brooks Range (the North Slope) have led to confusion over its past, present, and predicted future distributions. To determine if L. othus occurs or historically occurred on the North Slope, we surveyed museum collections, vetted observational accounts, and produced a spatial distribution model based on the resulting georeferenced records. We located a historic specimen long presumed lost that suggests the occurrence of L. othus on the North Slope as recently as the late 1800s. We also uncovered evidence of L. othus and (or) Mountain Hare (Lepus timidus Linnaeus 1758) on several islands in the Bering Sea, raising the possibility of recurring gene flow between these closely related species across seasonal ice connecting Asia and North America. While our results paint a more complete picture of the current distribution of L. othus, persistent uncertainties surrounding its taxonomic status and potential northward range shift onto lands reserved for oil and gas development call for additional study.
On the nature of the neutrino
Authors: Romero R.
Published: June 2016

Assuming that one neutrino type with definite mass is described by a massive Dirac field operator, it is shown that the physical one-particle states for particles and antiparticles can be rotated to each other, irrespective of their helicity. This result is used to prove that the neutrino must necessarily be a Majorana particle.
Quantum reduced loop gravity and the foundation of loop quantum cosmology
Authors: Alesci Emanuele , Cianfrani Francesco
Published: June 2016

Quantum reduced loop gravity is a promising framework for linking loop quantum gravity and the effective semiclassical dynamics of loop quantum cosmology. We review its basic achievements and its main perspectives, outlining how it provides a quantum description of the Universe in terms of a cuboidal graph which constitutes the proper framework for applying loop techniques in a cosmological setting.
Diffeomorphism invariant cosmological symmetry in full quantum gravity
Authors: Beetle Christopher , Engle Jonathan S. , Hogan Matthew E. , Mendonça Phillip
Published: June 2016

This paper summarizes a new proposal to define rigorously a sector of loop quantum gravity at the diffeomorphism invariant level corresponding to homogeneous and isotropic cosmologies, thereby enabling a detailed comparison of results in loop quantum gravity and loop quantum cosmology. The key technical steps we have completed are (a) to formulate conditions for homogeneity and isotropy in a diffeomorphism covariant way on the classical phase-space of general relativity, and (b) to translate these conditions consistently using well-understood techniques to loop quantum gravity. Some additional steps, such as constructing a specific embedding of the Hilbert space of loop quantum cosmology into a space of (distributional) states in the full theory, remain incomplete. However, we also describe, as a proof of concept, a complete analysis of an analogous embedding of homogeneous and isotropic loop quantum cosmology into the quantum Bianchi I model of Ashtekar and Wilson-Ewing. Details will appear in a pair of forthcoming papers.
Gates vs. Splitters
Authors: Deb Arighna , Wille Robert , Keszöcze Oliver , Hillmich Stefan , Drechsler Rolf
Published: June 2016

Optical circuits are considered a promising emerging technology for applications in ultra-high-speed networks or interconnects. However, the development of (automatic) synthesis approaches for such circuits is still in its infancy. Although first generic and automatic synthesis approaches have been proposed, no clear understanding exists yet on how to keep the costs of the resulting circuits as small as possible. In the domain of optical circuits, this is particularly interesting for the number of gates and the effect of so-called splitters to the signal strength. In this work, we investigate this relation by considering a variety of (existing as well as proposed) synthesis approaches for optical circuits. Our investigations show that reducing the number of gates and reducing the number of splitters are contradictory optimization objectives. Furthermore, the performance of synthesis guided with respect to gate efficiency as well as synthesis guided with respect to splitter freeness is evaluated and an overhead factor between the contradictory metrics is experimentally determined.
In Situ and In Vivo Molecular Analysis by Coherent Raman Scattering Microscopy
Authors: Liao Chien-Sheng , Cheng Ji-Xin
Published: June 2016

Coherent Raman scattering (CRS) microscopy is a high-speed vibrational imaging platform with the ability to visualize the chemical content of a living specimen by using molecular vibrational fingerprints. We review technical advances and biological applications of CRS microscopy. The basic theory of CRS and the state-of-the-art instrumentation of a CRS microscope are presented. We further summarize and compare the algorithms that are used to separate the Raman signal from the nonresonant background, to denoise a CRS image, and to decompose a hyperspectral CRS image into concentration maps of principal components. Important applications of single-frequency and hyperspectral CRS microscopy are highlighted. Potential directions of CRS microscopy are discussed.
Microfluidic Devices for the Measurement of Cellular Secretion
Authors: Schrell Adrian M. , Mukhitov Nikita , Yi Lian , Wang Xue , Roper Michael G.
Published: June 2016

The release of chemical information from cells and tissues holds the key to understanding cellular behavior and dysfunction. The development of methodologies that can measure cellular secretion in a time-dependent fashion is therefore essential. Often these measurements are made difficult by the high-salt conditions of the cellular environment, the presence of numerous other secreted factors, and the small mass samples that are produced when frequent sampling is used to resolve secretory dynamics. In this review, the methods that we have developed for measuring hormone release from islets of Langerhans are dissected to illustrate the practical difficulties of studying cellular secretions. Other methods from the literature are presented that provide alternative approaches to particularly challenging areas of monitoring cellular secretion. The examples presented in this review serve as case studies and should be adaptable to other cell types and systems for unique applications.
Differentiation of human bronchial epithelial cells: role of hydrocortisone in development of ion transport pathways involved in mucociliary clearance
Authors: Zaidman Nathan A. , Panoskaltsis-Mortari Angela , O'Grady Scott M.
Published: June 2016

Glucocorticoids strongly influence the mucosal-defense functions performed by the bronchial epithelium, and inhaled corticosteroids are critical in the treatment of patients with inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. A common pathology associated with these diseases is reduced mucociliary clearance, a defense mechanism involving the coordinated transport of salt, water, and mucus by the bronchial epithelium, ultimately leading to retention of pathogens and particles in the airways and to further disease progression. In the present study we investigated the role of hydrocortisone (HC) in differentiation and development of the ion transport phenotype of normal human bronchial epithelial cells under air-liquid interface conditions. Normal human bronchial epithelial cells differentiated in the absence of HC (HC0) showed significantly less benzamil-sensitive short-circuit current than controls, as well as a reduced response after stimulation with the selective β2-adrenergic receptor agonist salbutamol. Apical membrane localization of epithelial Na+ channel α-subunits was similarly reduced in HC0 cells compared with controls, supporting a role of HC in the trafficking and density of Na+ channels in the plasma membrane. Additionally, glucocorticoid exposure during differentiation regulated the transcription of cystic fibrosis transmembrane conductance regulator and β2-adrenergic receptor mRNAs and appeared to be necessary for the expression of cystic fibrosis transmembrane conductance regulator-dependent anion secretion in response to β2-agonists. HC had no significant effect on surface cell differentiation but did modulate the expression of mucin mRNAs. These findings indicate that glucocorticoids support mucosal defense by regulating critical transport pathways essential for effective mucociliary clearance.
In vitro characterization of noradrenergic modulation of chemosensitive neurons in the retrotrapezoid nucleus
Authors: Kuo Fu-Shan , Falquetto Bárbara , Chen Dawei , Oliveira Luiz M. , Takakura Ana C. , Mulkey Daniel K.
Published: June 2016

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO2/H+changes and serve as an integration center for other autonomic centers, including brain stem noradrenergic neurons. Norepinephrine (NE) contributes to respiratory control and chemoreception, and, since disruption of NE signaling may contribute to several breathing disorders, we sought to characterize effects of NE on RTN chemoreception. All neurons included in this study responded similarly to CO2/H+but showed differential sensitivity to NE; we found that NE activated (79%), inhibited (7%), or had no effect on activity (14%) of RTN chemoreceptors. The excitatory effect of NE on RTN chemoreceptors was dose dependent, retained in the presence of neurotransmitter receptor blockers, and could be mimicked and blocked by pharmacological manipulation of α1-adrenergic receptors (ARs). In addition, NE-activation was blunted by XE991 (KCNQ channel blocker), and partially occluded the firing response to serotonin, suggesting involvement of KCNQ channels. However, in whole cell voltage clamp, activation of α1-ARs decreased outward current and conductance by what appears to be a mixed effect on multiple channels. The inhibitory effect of NE on RTN chemoreceptors was blunted by an α2-AR antagonist. A third group of RTN chemoreceptors was insensitive to NE. We also found that chemosensitive RTN astrocytes do not respond to NE with a change in voltage or by releasing ATP to enhance activity of chemosensitive neurons. These results indicate NE modulates subsets of RTN chemoreceptors by mechanisms involving α1- and α2-ARs.
Validating silicon polytrodes with paired juxtacellular recordings: method and dataset
Authors: Neto Joana P. , Lopes Gonçalo , Frazão João , Nogueira Joana , Lacerda Pedro , Baião Pedro , Aarts Arno , Andrei Alexandru , Musa Silke , Fortunato Elvira , Barquinha Pedro , Kampff Adam R.
Published: June 2016

Cross-validating new methods for recording neural activity is necessary to accurately interpret and compare the signals they measure. Here we describe a procedure for precisely aligning two probes for in vivo “paired-recordings” such that the spiking activity of a single neuron is monitored with both a dense extracellular silicon polytrode and a juxtacellular micropipette. Our new method allows for efficient, reliable, and automated guidance of both probes to the same neural structure with micrometer resolution. We also describe a new dataset of paired-recordings, which is available online. We propose that our novel targeting system, and ever expanding cross-validation dataset, will be vital to the development of new algorithms for automatically detecting/sorting single-units, characterizing new electrode materials/designs, and resolving nagging questions regarding the origin and nature of extracellular neural signals.
Variability in Dust Observed over China Using A-Train CALIOP Instrument
Authors: Xu Hui , Zheng Fengjie , Zhang Wenhao
Published: June 2016

Patterns of dust aerosol variation over China are analyzed using A-Train CALIOP and precipitation, soil moisture, and vegetation coverage datasets during the period of 2007 and 2014. Spatially, dust is mostly prominent over northwestern China, with the highest and most widespread dust activities being in Taklimakan Desert. Dust is generally distributed across the atmosphere up to 5 km altitude, with a peak of DAFOD around 3 km. The dust layer has a significant geographical and seasonal drifting, with higher altitude in spring and summer and dust source regions (between 3 km and 5 km). Additionally, single dust layer is more often observed in a vertical column. Temporally, high amounts of dust aerosol (C-DAFOD as high as 0.08) experienced in spring subsequently continuous decrease until the spring of next year. The correlation coefficients between the latitude averaged column integrated dust aerosol feature optical depth (C-DAFOD) and precipitation, soil moisture, and vegetation coverage are −0.65, −0.81, and −0.77, respectively. The correlation coefficients of seasonal mean C-DAFOD with the three factors are −0.15, −0.67, and −0.35, respectively. The analysis showed dust and the other three factors are negatively correlated. Overall, dust over China shows considerable spatial, temporal, and vertical variations.
Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα
Authors: Yang Jing , Wang Fengyue , Sun Weiju , Dong Yanli , Li Mingyu , Fu Lu
Published: June 2016

Despite the importance of testosterone as a metabolic hormone, its effects on myocardial metabolism in the ischemic heart remain unclear. Myocardial ischemia leads to metabolic remodeling, ultimately resulting in ATP deficiency and cardiac dysfunction. In the present study, the effects of testosterone replacement on the ischemic heart were assessed in a castrated rat myocardial infarction model established by ligating the left anterior descending coronary artery 2 weeks after castration. The results of real-time PCR and Western blot analyses showed that peroxisome proliferator-activated receptorα(PPARα) decreased in the ischemic myocardium of castrated rats, compared with the sham-castration group, and the mRNA expression of genes involved in fatty acid metabolism (the fatty acid translocase CD36, carnitine palmitoyltransferase I, and medium-chain acyl-CoA dehydrogenase) and glucose transporter-4 also decreased. A decline in ATP levels in the castrated rats was accompanied by increased cardiomyocyte apoptosis and fibrosis and impaired cardiac function, compared with the sham-castration group, and these detrimental effects were reversed by testosterone replacement. Taken together, our findings suggest that testosterone can modulate myocardial metabolic remodeling by upregulating PPARαafter myocardial infarction, exerting a protective effect on cardiac function.
Relationship between Peeled Internal Limiting Membrane Area and Anatomic Outcomes following Macular Hole Surgery: A Quantitative Analysis
Authors: Goker Yasin Sakir , Koc Mustafa , Yuksel Kemal , Yazici Ahmet Taylan , Demir Abdulvahit , Gunes Hasan , Ozpinar Yavuz
Published: June 2016

Purpose. To quantitatively evaluate the effects of peeled internal limiting membrane (ILM) area and anatomic outcomes following macular hole surgery using spectral domain optical coherence tomography (SD-OCT).Methods. Forty-one eyes in 37 consecutive patients with idiopathic, Gass stage 3-4 macular hole (MH) were enrolled in this retrospective comparative study. All patients were divided into 2 groups according to anatomic success or failure. Basal MH diameter, peeled ILM area, and MH height were calculated using SD-OCT. Other prognostic parameters, including age, stage, preoperative BCVA, and symptom duration were also assessed.Results. Thirty-two cases were classified as anatomic success, and 9 cases were classified as anatomic failure. Peeled ILM area was significantly wider and MH basal diameter was significantly less in the anatomic success group (p=0.024and 0.032, resp.). Other parameters did not demonstrate statistical significance.Conclusion. The findings of the present study show that the peeled ILM area can affect the anatomic outcomes of MH surgery.
Plurihormonal Cosecretion by a Case of Adrenocortical Oncocytic Neoplasm
Authors: Corrales J. J. , Robles-Lázaro C. , Sánchez-Marcos A. I. , González-Sánchez M. C. , Antúnez-Plaza P. , Miralles J. M.
Published: June 2016

Adrenocortical oncocytic neoplasms (oncocytomas) are extremely rare; only approximately 159 cases have been described so far. The majority are nonfunctional and benign. We describe an unusual case of a functional oncocytoma secreting an excess of glucocorticoids (cortisol) and androgens (androstenedione and DHEAS), a pattern of plurihormonal cosecretion previously not reported in men, presenting with endocrine manifestations of Cushing’s syndrome. The neoplasm was considered to be of uncertain malignant potential (borderline) according to the Lin-Weiss-Bisceglia criteria.
A Case-Control Study and Meta-Analysis RevealBDNFVal66Met Is a Possible Risk Factor for PTSD
Authors: Bruenig Dagmar , Lurie Janine , Morris Charles P. , Harvey Wendy , Lawford Bruce , Young Ross McD , Voisey Joanne
Published: June 2016

Posttraumatic stress disorder (PTSD) is a debilitating condition that develops in some people after exposure to a traumatic event. Brain-derived neurotrophic factor (BDNF) is highly expressed in the mammalian brain and is thought to be involved in learning and memory processes. A nonsynonymous polymorphism in theBDNFgene, rs6265 (Val66Met), has been hypothesised to be associated with PTSD. Association studies examining the Val66Met polymorphism and PTSD have been inconclusive, likely due to the variability in type of trauma exposure analysed. Vietnam veterans (n=257) screened for PTSD and controlled for trauma exposure were genotyped forBDNFVal66Met. The association was not significant so we incorporated our data into a meta-analysis to obtain greater statistical power. A comprehensive search of more than 1237 articles revealed eight additional studies suitable for meta-analysis (n=3625). A random-effects meta-analysis observed a potential protective factor of the Val/Val genotype. After removing two studies with violation of Hardy-Weinberg equilibrium, findings for the Val/Val genotype reached significance. Subgroup analyses confirmed a trend for this finding. Limitations of some studies that inform this meta-analysis include poorly screened controls and a lack of examination of population stratification. Effectively designed studies should inform this line of research in the future.
A Fast Framework for Abrupt Change Detection Based on Binary Search Trees and Kolmogorov Statistic
Authors: Qi Jin-Peng , Qi Jie , Zhang Qing
Published: June 2016

Change-Point (CP) detection has attracted considerable attention in the fields of data mining and statistics; it is very meaningful to discuss how to quickly and efficiently detect abrupt change from large-scale bioelectric signals. Currently, most of the existing methods, like Kolmogorov-Smirnov (KS) statistic and so forth, are time-consuming, especially for large-scale datasets. In this paper, we propose a fast framework for abrupt change detection based on binary search trees (BSTs) and a modified KS statistic, named BSTKS (binary search trees and Kolmogorov statistic). In this method, first, two binary search trees, termed as BSTcA and BSTcD, are constructed by multilevel Haar Wavelet Transform (HWT); second, three search criteria are introduced in terms of the statistic and variance fluctuations in the diagnosed time series; last, an optimal search path is detected from the root to leaf nodes of two BSTs. The studies on both the synthetic time series samples and the real electroencephalograph (EEG) recordings indicate that the proposed BSTKS can detect abrupt change more quickly and efficiently than KS,t-statistic (t), and Singular-Spectrum Analyses (SSA) methods, with the shortest computation time, the highest hit rate, the smallest error, and the highest accuracy out of four methods. This study suggests that the proposed BSTKS is very helpful for useful information inspection on all kinds of bioelectric time series signals.
Comparisons of Auditory Performance and Speech Intelligibility after Cochlear Implant Reimplantation in Mandarin-Speaking Users
Authors: Hwang Chung-Feng , Ko Hui-Chen , Tsou Yung-Ting , Chan Kai-Chieh , Fang Hsuan-Yeh , Wu Che-Ming
Published: June 2016

Objectives. We evaluated the causes, hearing, and speech performance before and after cochlear implant reimplantation in Mandarin-speaking users.Methods. In total, 589 patients who underwent cochlear implantation in our medical center between 1999 and 2014 were reviewed retrospectively. Data related to demographics, etiologies, implant-related information, complications, and hearing and speech performance were collected.Results. In total, 22 (3.74%) cases were found to have major complications. Infection (n=12) and hard failure of the device (n=8) were the most common major complications. Among them, 13 were reimplanted in our hospital. The mean scores of the Categorical Auditory Performance (CAP) and the Speech Intelligibility Rating (SIR) obtained before and after reimplantation were 5.5 versus 5.8 and 3.7 versus 4.3, respectively. The SIR score after reimplantation was significantly better than preoperation.Conclusions. Cochlear implantation is a safe procedure with low rates of postsurgical revisions and device failures. The Mandarin-speaking patients in this study who received reimplantation had restored auditory performance and speech intelligibility after surgery. Device soft failure was rare in our series, calling attention to Mandarin-speaking CI users requiring revision of their implants due to undesirable symptoms or decreasing performance of uncertain cause.
Improving Surgical Access in Rural Africa through a Surgical Camp Model
Authors: Galukande M. , Kituuka O. , Elobu E. , Jombwe J. , Sekabira J. , Butler Elissa , Faulal J.
Published: June 2016

Introduction. Surgical camps are preplanned activities where volunteer surgical teams congregate at specified place(s) and perform a wide range of mostly elective procedures for a limited period of time. This is usually at no cost to the patients, who belong to vulnerable (poor and hard to reach) communities. We describe a surgical camp model and its challenges as a means of improving access to surgical services.Methods. A cross-sectional descriptive study. Data from a recent Association of Surgeons of Uganda surgical camp were collected and analyzed for demographics, costs, procedure types, and rates and, in addition, challenges encountered and solutions. Personnel that participated in this exercise included specialist surgeons, surgical residents, medical officers, clinical officers, anesthetists, and theater nurses (a total of 121 staff).Results. In total, 551 procedures were performed during a four-day-long camp. Mean age was 35 years (SD 23), M : F ratio was 2 : 1. Herniorrhaphy, skin lump excision, hydrocelectomy, and thyroidectomy formed 81% of all the procedures. Average cost per procedure was $73 USD.Conclusion. Surgical camps offer increased access to surgical services to vulnerable populations. Hernias and goiters were most common. Surgical camps should become an integral part of the Health Service delivery in low-resourced environments.
Symptoms and Etiological Attribution: A Cross-Sectional Study in Mexican Outpatients with Psychosis and Their Relatives
Authors: Gómez-de-Regil Lizzette , Ros-Morente Agnès , Rodríguez-Hansen Gisela
Published: June 2016

This cross-sectional study aimed at identifying the most common attributions of their mental disorder in a Mexican patients who have experienced psychosis and their relatives and exploring how having experienced or not characteristic psychotic symptoms and their present clinical status might affect their etiological attributions. Past and current symptom profiles of 66 patients were as assessed with the SCID-I (Structured Clinical Interview for DSM-IV Axis I Disorders) and the PANSS (Positive and Negative Syndrome Scale), respectively. The etiological attribution of psychosis of patients (n=62) and the relatives (n=65) was assessed with the Angermeyer and Klusmann scale comprising 30 items into five categories: biology, personality, family, society, and esoteric. Patients and relatives attribute psychosis mainly to social factors. Relatives’ attributions were not influenced by clinical profile of patients, whereas in the case of patients it was only current clinical status that showed a difference, with those in nonremission scoring higher personality and family factors. Acknowledging patients’ and relatives’ beliefs about mental disorders at onset and later on is particularly important in psychosis, a mental condition with severe and/or persistent symptoms, in order to promote better involvement in treatment and in consequence efficacy and recovery.
A Laser Fabrication of Magnetic Micromachines by Using Optimized Photosensitive Ferrofluids
Authors: Tian Ye , Shao Xiangxin
Published: June 2016

We report here a laser fabrication of magnetic micromachines by using optimized photosensitive ferrofluids. Fe3O4nanoparticles were prepared by thermal decomposition and subsequent ligand exchange. And then, they were dispersed into photoresist. As a representative illustration, a magnetic microturbine with high surface flatness was fabricated, and its rotation speed could reach as high as 400 rpm under revolving magnetic field.
Implementation of Real-Time Machining Process Control Based on Fuzzy Logic in a New STEP-NC Compatible System
Authors: Hu Po , Han Zhenyu , Fu Yunzhong , Fu Hongya
Published: June 2016

Implementing real-time machining process control at shop floor has great significance on raising the efficiency and quality of product manufacturing. A framework and implementation methods of real-time machining process control based on STEP-NC are presented in this paper. Data model compatible with ISO 14649 standard is built to transfer high-level real-time machining process control information between CAPP systems and CNC systems, in which EXPRESS language is used to define new STEP-NC entities. Methods for implementing real-time machining process control at shop floor are studied and realized on an open STEP-NC controller, which is developed using object-oriented, multithread, and shared memory technologies conjunctively. Cutting force at specific direction of machining feature in side mill is chosen to be controlled object, and a fuzzy control algorithm with self-adjusting factor is designed and embedded in the software CNC kernel of STEP-NC controller. Experiments are carried out to verify the proposed framework, STEP-NC data model, and implementation methods for real-time machining process control. The results of experiments prove that real-time machining process control tasks can be interpreted and executed correctly by the STEP-NC controller at shop floor, in which actual cutting force is kept around ideal value, whether axial cutting depth changes suddenly or continuously.
BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer
Authors: Bansal Nitu , Bartucci Monica , Yusuff Shamila , Davis Stephani , Flaherty Kathleen , Huselid Eric , Patrizii Michele , Jones Daniel , Cao Liangxian , Sydorenko Nadiya , Moon Young-Choon , Zhong Hua , Medina Daniel , Kerrigan John , Stein Mark N. , Kim Isaac Y. , Davis Thomas W. , DiPaola Robert S. , Bertino Joseph , Sabaawy Hatem E.
Published: June 2016

Purpose: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach.

Experimental Design: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1.

Results: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell–like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor–directed therapies, without toxic effects on normal tissues.

Conclusions: Our data offer a paradigm for targeting TICs and support the development of BMI-1–targeting therapy for a more effective prostate cancer treatment. Clin Cancer Res; 22(24); 6176–91. ©2016 AACR.
Toward Concurrent Testing for Somatic and Germline Variants in Cancer Patients
Authors: Mandelker Diana
Published: June 2016

Sequencing for somatic alterations in patients' tumors is being increasingly clinically implemented to detect mutations that may guide therapy. Germline analysis of a cohort of patients undergoing tumor sequencing with matched normal has revealed that a small but significant percentage of these patients have germline variants that confer cancer susceptibility. Clin Cancer Res; 22(16); 3987–8. ©2016 AACR.

See related article by Seifert et al., p. 4087
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma
Authors: Carlsten Mattias , Korde Neha , Kotecha Ritesh , Reger Robert , Bor Simona , Kazandjian Dickran , Landgren Ola , Childs Richard W.
Published: June 2016

Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.

Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.

Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.

Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211–22. ©2016 AACR.

See related commentary by Felices and Miller, p. 5161
miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization
Authors: Raimo Monica , Orso Francesca , Grassi Elena , Cimino Daniela , Penna Elisa , De Pittà Cristiano , Stadler Michael B. , Primo Luca , Calautti Enzo , Quaglino Pietro , Provero Paolo , Taverna Daniela
Published: June 2016

Malignant melanoma is the most aggressive form of skin cancer; therefore, it is crucial to disclose its underlying molecular mechanisms. MicroRNAs (miRNAs) are small endogenous noncoding RNAs able to posttranscriptionally downregulate the expression of direct target genes. Using a melanoma progression model, miR-146a was identified as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth, while it suppresses dissemination. It was determined that miR-146a coordinated melanoma cell growth by its direct targets lunatic fringe (LFNG) and NUMB, which operate on the NOTCH/PTEN/Akt pathway; while inhibition of metastasis formation was linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlated with melanoma recurrence and was enriched in both patient-derived melanoma and cutaneous metastasis specimens, while its direct targets were depleted. However, miR-146a levels drop in circulating tumor cells (CTCs), suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biologic functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions.

Implications: miR-146a controls melanoma progression in a dual way, promoting growth and inhibiting dissemination; however, it is poorly expressed in CTCs, resulting in overall tumor spreading and distant-site colonization. Mol Cancer Res; 14(6); 548–62. ©2016 AACR.
Simvastatin induces the apoptosis of normal vascular smooth muscle through the disruption of actin integrity via the impairment of RhoA/ Rac-1 activity
Authors: Kang Seojin , Kim Keunyoung , Noh Ji-Yoon , Jung Yeryeon , Bae Ok-Nam , Lim Kyung-Min , Chung Jin-Ho
Published: June 2016

Statins, lipid-lowering agents for the prevention of atherosclerosis and fatal coronary heart diseases, have pleiotropic modalities on the function and physiology of vascular smooth muscle that include anti-contractile and pro-apoptotic effects. These effects were suggested to stem from the inhibition of small GTPase Rho A, but they are largely regarded as distinct and unrelated. Recently, we discovered that simvastatin causes both contractile dysfunction and apoptosis of vascular smooth muscle cells (VSMCs), reflecting that they may be closely related, yet their connecting link remains unexplained. Here, we elaborated the mechanism underlying simvastatin-induced apoptosis of normal VSMCs in connection with contractile dysfunction. Repeated oral administration of simvastatin to rats in vivo resulted in contractile dysfunction and apoptosis of vascular smooth muscle, of which pattern was well reproduced in rat VSMCs in vitro. Of note, contractile dysfunction and apoptosis occurred in concerted manners both in vivo and in vitro in the aspects of time course and dose of exposure. In rat VSMCs, simvastatin impaired the activation of small GTPases, RhoA along with Rac-1, which resulted in the disruption of actin integrity, a pivotal factor both for the generation of contractile force and survival of VSMCs. In line with the disruption of actin integrity, Bmf, a pro-apoptotic factor bound to intact actin, dissociated and translocated into mitochondria, which corresponded well with the dissipation of mitochondrial membrane potential, caspase-3 activation and ultimately apoptosis. These events were all rescued by an actin stabilisation agent, jasplakinolide as well as geranylgeraniol, indicating that damages of the actin integrity from disrupted activation of RhoA/ Rac-1 lies at the center of simvastatin-induced contractile dysfunction and apoptosis in vascular smooth muscle.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Quality and predictors of anticoagulant control with vitamin K antagonist for stroke prevention in atrial fibrillation
Authors: Parakramawansha Ruwan , Quinn Terence J. , Tait Robert C. , Wilson Matthew R.
Published: June 2016

Supplementary Material to this article is available online at www.thrombosis-online.com.
Oxidative stress and thromboxane-dependent platelet activation in inflammatory bowel disease: effects of anti-TNF-α treatment
Authors: Guerci Marco , Simeone Paola , Ardizzone Sandro , Massari Alessandro , Giuffrida Paolo , Tripaldi Romina , Malara Alessandro , Liani Rossella , Gurini Evelyn , Aronico Nicola , Balduini Alessandra , Sabatino Antonio Di , Santilli Francesca , Corazza Gino Roberto , Davì Giovanni
Published: June 2016

Patients with inflammatory bowel disease (IBD) are at higher risk of venous thromboembolism and coronary artery disease despite having a lower burden of traditional risk factors. Platelets from IBD patients release more soluble CD40 ligand (CD40L), and this has been implicated in IBD platelet hyper-activation. We here measured the urinary F2-isoprostane 8-iso-prostaglandin (PG)2α (8-iso-PGF2α), urinary 11–dehydro–thromboxane (TX) B2 (11-dehydro–TXB2) and plasma CD40L in IBD patients, and explored the in vitro action of anti-tumour necrosis factor (TNF)–α antibody infliximab on IBD differentiating megakaryocytes. Urinary and blood samples were collected from 124 IBD patients and 37 healthy subjects. Thirteen IBD patients were also evaluated before and after 6–week infliximab treatment. The in vitro effect of infliximab on patient-derived megakaryocytes was evaluated by immunoflorescence microscopy and by flow cytometry. IBD patients had significantly (p<0.0001) higher urinary 8–iso–PGF2α and 11–dehydro–TXB2 as well as plasma CD40L levels than controls, with active IBD patients displaying higher urinary and plasma values when compared to inactive patients in remission. A 6-week treatment with infliximab was associated with a significant reduction of the urinary excretion of 8–iso–PGF2α and 11–dehydro–TXB2 (p=0.008) and plasma CD40L (p=0.001). Infliximab induced significantly rescued pro-platelet formation by megakaryocytes derived from IBD patients but not from healthy controls. Our findings provide evidence for enhanced in vivo TX–dependent platelet activation and lipid peroxidation in IBD patients. Anti-TNF–α therapy with infliximab down-regulates in vivo isoprostane generation and TX biosynthesis in responder IBD patients. Further studies are needed to clarify the implication of infliximab induced-proplatelet formation from IBD megakaryocytes.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Cost-Effectiveness of Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation Based on Results From PROTECT AF Versus PREVAIL
Authors: Freeman James V. , Hutton David W. , Barnes Geoffrey D. , Zhu Ruo P. , Owens Douglas K. , Garber Alan M. , Go Alan S. , Hlatky Mark A. , Heidenreich Paul A. , Wang Paul J. , Al-Ahmad Amin , Turakhia Mintu P.
Published: June 2016

Background—

Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown varying results, and its cost effectiveness compared with anticoagulation has not been evaluated using all available contemporary trial data.

Methods and Results—

We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation (PROTECT AF) and Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation (PREVAIL) randomized trials. Using data from PROTECT AF, the incremental cost-effectiveness ratios compared with warfarin and dabigatran were $20 486 and $23 422 per quality-adjusted life year, respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (8.44, 8.54, and 8.59 quality-adjusted life years, respectively) and more costly. At a willingness-to-pay threshold of $50 000 per quality-adjusted life year, LAA closure was cost effective 90% and 9% of the time under PROTECT AF and PREVAIL assumptions, respectively. These results were sensitive to the rates of ischemic stroke and intracranial hemorrhage for LAA closure and medical anticoagulation.

Conclusions—

Using data from the PROTECT AF trial, LAA closure with the Watchman device was cost effective; using PREVAIL trial data, Watchman was more costly and less effective than warfarin and dabigatran. PROTECT AF enrolled more patients and has substantially longer follow-up time, allowing greater statistical certainty with the cost-effectiveness results. However, longer-term trial results and postmarketing surveillance of major adverse events will be vital to determining the value of the Watchman in clinical practice.
Plaque Structural Stress Estimations Improve Prediction of Future Major Adverse Cardiovascular Events After Intracoronary Imaging
Authors: Brown Adam J. , Teng Zhongzhao , Calvert Patrick A. , Rajani Nikil K. , Hennessy Orla , Nerlekar Nitesh , Obaid Daniel R. , Costopoulos Charis , Huang Yuan , Hoole Stephen P. , Goddard Martin , West Nick E.J. , Gillard Jonathan H. , Bennett Martin R.
Published: June 2016

Background—

Although plaque rupture is responsible for most myocardial infarctions, few high-risk plaques identified by intracoronary imaging actually result in future major adverse cardiovascular events (MACE). Nonimaging markers of individual plaque behavior are therefore required. Rupture occurs when plaque structural stress (PSS) exceeds material strength. We therefore assessed whether PSS could predict future MACE in high-risk nonculprit lesions identified on virtual-histology intravascular ultrasound.

Methods and Results—

Baseline nonculprit lesion features associated with MACE during long-term follow-up (median: 1115 days) were determined in 170 patients undergoing 3-vessel virtual-histology intravascular ultrasound. MACE was associated with plaque burden ≥70% (hazard ratio: 8.6; 95% confidence interval, 2.5–30.6;
P
<0.001) and minimal luminal area ≤4 mm
2
(hazard ratio: 6.6; 95% confidence interval, 2.1–20.1;
P
=0.036), although absolute event rates for high-risk lesions remained <10%. PSS derived from virtual-histology intravascular ultrasound was subsequently estimated in nonculprit lesions responsible for MACE (n=22) versus matched control lesions (n=22). PSS showed marked heterogeneity across and between similar lesions but was significantly increased in MACE lesions at high-risk regions, including plaque burden ≥70% (13.9±11.5 versus 10.2±4.7;
P
<0.001) and thin-cap fibroatheroma (14.0±8.9 versus 11.6±4.5;
P
=0.02). Furthermore, PSS improved the ability of virtual-histology intravascular ultrasound to predict MACE in plaques with plaque burden ≥70% (adjusted log-rank,
P
=0.003) and minimal luminal area ≤4 mm
2
(
P
=0.002). Plaques responsible for MACE had larger superficial calcium inclusions, which acted to increase PSS (
P
<0.05).

Conclusions—

Baseline PSS is increased in plaques responsible for MACE and improves the ability of intracoronary imaging to predict events. Biomechanical modeling may complement plaque imaging for risk stratification of coronary nonculprit lesions.