bluuebunny/crossref_metadata_2025 huggingface dataset:
Picture-to-puncture time in acute stroke endovascular intervention: are we getting faster?
Authors: van Heerden J , Yan B , Churilov L , Dowling R J , Mitchell P J
Published: June 2014

Background

In acute stroke management, time efficiency in the continuum of patient management is critical. We aimed to determine if implementation of system improvements at our institution translated to reduced picture-to-puncture (P2P) times over a 6-year period.

Methods

We conducted a single-center retrospective analysis using a prospective acute stroke database of patients treated with intra-arterial therapy from October 2007 to October 2013. Patient demographics, stroke severity, neuroimaging and treatment time points were collected. Annual P2P times, defined as the interval between pretreatment neuroimaging (picture) and commencement of intra-arterial therapy (puncture), were assessed and compared.

Results

From 2007 to 2013 a total of 189 patients were identified, of which 181 met the study criteria. At initial presentation, median baseline NIH Stroke Severity score was 17.00 (IQR 11.00–22.00). Annual median P2P times decreased from 171 to 123.5 min, showing a median decrease of 11.5 min per annum (95% CI −23.9 to 0.9) and trending towards statistical significance (p=0.069). Plotted data revealed longer P2P times in instances where stroke onset or CT acquisition times were out-of-hours. Using median regression modeling, the annual decrease in P2P median time reached statistical significance when independently adjusting for CT acquisition time (13.5 min P2P median time reduction, 95% CI −27.0 to −0.1, p=0.048) and for stroke onset time (14.5 min annual P2P median time reduction, 95% CI −26.1 to −2.8, p=0.015).

Conclusions

As a consequence of systems improvement at our institution, we were able to demonstrate improved annual median P2P times from 2007 to 2013.
Understanding frequency response of thermal micropumps using electrical network analogy
Authors: Bardaweel Hamzeh. K.
Published: June 2014

In this article the frequency response of a thermal micropump is investigated using electrical network analogy modeling technique. This technique is based on dividing the micropump into subsystems and representing each subsystem using the equivalent network analogy. Obtained mathematical models of subsystems are then represented using transfer functions and block diagrams. As an example, thermopneumatic micropump is considered. Model simulation suggests an increase in the net flow rates of the micropump as the operating frequencies increased, until a first cut-off frequency is reached. A second cut-off frequency is observed with further increase in operating frequencies. Model simulations are consistent with qualitative experimental trends reported in the literature. The model is used to obtain a relationship between cut-off frequencies and design properties of the micropump. Model simulations show that lower cut-off frequency is related to mechanical properties of the thermopneumatic micropump, including stiffness and damping. Upper cut-off frequency is related to thermal properties of the thermopneumatic micropump, including thermal conductivity, heat capacity, and working fluid density.
Early markers of occult megaloblastosis for low-cost detection of hyperhomocysteinemia in patients with ischaemic stroke: preventive approach for primary health care
Authors: Neogi Sohini Sengupta , Thomas Monica , Sharma Archna , Kumar Jaishree , Khanduri Uma
Published: June 2014

Recent studies have focussed on the association between elevated homocysteine levels with megaloblastic changes and thromboembolic events, but the relationship between occult megaloblastosis (with normal haemoglobin levels) and ischaemic stroke has not been widely explored. The objective of this study is to establish a simple and economical marker for the detection of occult megaloblastosis at the community health care level in developing countries. A hundred patients who met the inclusion criteria were studied. At the 5% level of significance, the levels of cobalamin and folate were significantly lower, while the number of hypersegmented neutrophils on the peripheral smear was higher in patients from Group A (70 patients with high homocysteine) compared with the patients in Group B (30 patients with normal homocysteine). Forty-five (64.2%) of the 70 patients in Group A showed hypersegmentation of neutrophils in the peripheral smear. The high cost and difficulty in performing the vitamin assays limit their use as early markers of megaloblastosis. Hence, we conclude that in developing countries, the detection of hypersegmented neutrophils can be used at the primary healthcare level for early diagnosis of occult megaloblastosis, so that early therapeutic interventions with vitamins can prevent attacks of hyperhomocysteinemia-induced ischaemic stroke.
Evidence of the big fix
Authors: Hamada Yuta , Kawai Hikaru , Kawana Kiyoharu
Published: June 2014

We give an evidence of the Big Fix. The theory of wormholes and multiverse suggests that the parameters of the Standard Model are fixed in such a way that the total entropy at the late stage of the universe is maximized, which we call the maximum entropy principle. In this paper, we discuss how it can be confirmed by the experimental data, and we show that it is indeed true for the Higgs vacuum expectation value vh. We assume that the baryon number is produced by the sphaleron process, and that the current quark masses, the gauge couplings and the Higgs self-coupling are fixed when we vary vh. It turns out that the existence of the atomic nuclei plays a crucial role to maximize the entropy. This is reminiscent of the anthropic principle, however it is required by the fundamental law in our case.
On the Casimir energy of the electromagnetic field in the dispersive and absorptive medium
Authors: Braun M. A.
Published: June 2014

The microscopic theory of the Casimir effect in the dielectric is studied in the framework when absorption is realized via a reservoir modeled by a set of oscillators with continuously distributed frequencies with the aim to see if the effects depend on the form of interaction with the reservoir. A simple case of the one-dimensional dielectric between two metallic plates is considered. Two possible models are investigated, the direct interaction of the electromagnetic field with the reservoir and indirect interaction via an intermediate oscillator imitating the atom. It is found that with the same dielectric constant the Casimir effect is different in these two cases, which implies that in the second model it cannot be entirely expressed via the dielectric constant as in the well-known Lifshitz formula.
CLUSTERING STOCK DATA FOR MULTI-OBJECTIVE PORTFOLIO OPTIMIZATION
Authors: LONG NGUYEN CONG , WISITPONGPHAN NAWAPORN , MEESAD PHAYUNG , UNGER HERWIG
Published: June 2014

Portfolio selection is a vital research field in modern finance. Multi-objective portfolio optimization problem is the portfolio selection process that results in the highest expected return rate and the lowest identified risk among the various financial assets. This paper proposes a model that can efficiently suggest a portfolio that is worth investing. First, a cluster analysis model is introduced in order to categorize a huge amount of stock data into several groups based on their associated return rate and the risk. Several validity indexes are used to select the optimal number of clusters/stocks to be included in the portfolio. Finally, the multi-objective genetic algorithm is used to build portfolio optimization with highest return rate and lowest risk. The proposed model is tested on the data obtained from the Stock Exchange of Thailand.
Nanoscale Methods for Single-Molecule Electrochemistry
Authors: Mathwig Klaus , Aartsma Thijs J. , Canters Gerard W. , Lemay Serge G.
Published: June 2014

The development of experiments capable of probing individual molecules has led to major breakthroughs in fields ranging from molecular electronics to biophysics, allowing direct tests of knowledge derived from macroscopic measurements and enabling new assays that probe population heterogeneities and internal molecular dynamics. Although still somewhat in their infancy, such methods are also being developed for probing molecular systems in solution using electrochemical transduction mechanisms. Here we outline the present status of this emerging field, concentrating in particular on optical methods, metal-molecule-metal junctions, and electrochemical nanofluidic devices.
Solid-Phase Biological Assays for Drug Discovery
Authors: Forsberg Erica M. , Sicard Clémence , Brennan John D.
Published: June 2014

In the past 30 years, there has been a significant growth in the use of solid-phase assays in the area of drug discovery, with a range of new assays being used for both soluble and membrane-bound targets. In this review, we provide some basic background to typical drug targets and immobilization protocols used in solid-phase biological assays (SPBAs) for drug discovery, with emphasis on particularly labile biomolecular targets such as kinases and membrane-bound receptors, and highlight some of the more recent approaches for producing protein microarrays, bioaffinity columns, and other devices that are central to small molecule screening by SPBA. We then discuss key applications of such assays to identify drug leads, with an emphasis on the screening of mixtures. We conclude by highlighting specific advantages and potential disadvantages of SPBAs, particularly as they relate to particular assay formats.
Neoliberalism
Authors: Ganti Tejaswini
Published: June 2014

Neoliberalism has been a popular concept within anthropological scholarship over the past decade; this very popularity has also elicited a fair share of criticism. This review examines current anthropological engagements with neoliberalism and explains why the concept has been so attractive for anthropologists since the millennium. It briefly outlines the history of neoliberal thought and explains how neoliberalism is different from late capitalism. Although neoliberalism is a polysemic concept with multiple referents, anthropologists have most commonly understood neoliberalism in two main ways: as a structural force that affects people's life-chances and as an ideology of governance that shapes subjectivities. Neoliberalism frequently functions as an index of the global political-economic order and allows for a vast array of ethnographic sites and topics to be contained within the same frame. However, as an analytical framework, neoliberalism can also obscure ethnographic particularities and foreclose certain avenues of inquiry.
The Coevolution of Galaxies and Supermassive Black Holes: Insights from Surveys of the Contemporary Universe
Authors: Heckman Timothy M. , Best Philip N.
Published: June 2014

We summarize what large surveys of the contemporary Universe have taught us about the physics and phenomenology of the processes that link the formation and evolution of galaxies with their central supermassive black holes. We present a picture in which the population of active galactic nuclei (AGNs) can be divided into two distinct populations. The radiative-mode AGNs are associated with black holes (BHs) that produce radiant energy powered by accretion at rates in excess of ∼1% of the Eddington limit. They are primarily associated with less massive BHs growing in high-density pseudobulges at a rate sufficient to produce the total mass budget in these BHs in ∼10 Gyr. The circumnuclear environment contains high-density cold gas and associated star formation. Major mergers are not the primary mechanism for transporting this gas inward; secular processes appear dominant. Stellar feedback is generic in these objects, and strong AGN feedback is seen only in the most powerful AGNs. In jet-mode AGNs the bulk of energetic output takes the form of collimated outflows (jets). These AGNs are associated with the more massive BHs in more massive (classical) bulges and elliptical galaxies. Neither the accretion onto these BHs nor star formation in their host bulge is significant today. These AGNs are probably fueled by the accretion of slowly cooling hot gas that is limited by the feedback/heating provided by AGN radio sources. Surveys of the high-redshift Universe paint a similar picture. Noting that the volume-averaged ratio of star formation to BH growth has remained broadly constant over the past 10 Gyrs, we argue that the processes that linked the cosmic evolution of galaxies and BHs are still at play today.
The Evolution of Galaxy Structure Over Cosmic Time
Authors: Conselice Christopher J.
Published: June 2014

I present a comprehensive review of the evolution of galaxy structure in the Universe from the first galaxies currently observable at z ∼ 6 down to galaxies observable in the local Universe. Observed changes in galaxy structures reveal formation processes that only galaxy structural analyses can provide. This pedagogical review provides a detailed discussion of the major methods used to study galaxies morphologically and structurally, including the well-established visual method for morphology; Sérsic fitting to measure galaxy sizes and surface brightness profile shapes; and nonparametric structural methods [such as the concentration (C), asymmetry (A), clumpiness (S) (CAS) method and the Gini/M20 parameters, as well as newer structural indices]. These structural indices measure fundamental properties of galaxies, such as their scale, star-formation rate, and ongoing merger activity. Extensive observational results demonstrate how broad galaxy morphologies and structures change with time up to z ∼ 3, from small, compact and peculiar systems in the distant Universe to the formation of the Hubble sequence, dominated by spirals and ellipticals. Structural methods accurately identify galaxies in mergers and allow measurements of the merger history out to z ∼ 3. I depict properties and evolution of internal structures of galaxies, such as bulges, disks, bars, and at z>1 large star-forming clumps. I describe the structure and morphologies of host galaxies of active galactic nuclei and starbursts/submillimeter galaxies, along with how morphological galaxy quenching occurs. The role of environment in producing structural changes in galaxies over cosmic time is also discussed. Galaxy sizes can also change with time, with measured sizes up to a factor of 2–5 smaller at high redshift at a given stellar mass. I conclude with a discussion of how the evolving trends, in sizes, structures, and morphologies, reveal the formation mechanisms behind galaxies and provides a new and unique way to test theories of galaxy formation.
Observational Clues to the Progenitors of Type Ia Supernovae
Authors: Maoz Dan , Mannucci Filippo , Nelemans Gijs
Published: June 2014

Type Ia supernovae (SNe Ia) are important distance indicators, element factories, cosmic-ray accelerators, kinetic-energy sources in galaxy evolution, and end points of stellar binary evolution. It has long been clear that a SN Ia must be the runaway thermonuclear explosion of a degenerate carbon-oxygen stellar core, most likely a white dwarf (WD). However, the specific progenitor systems of SNe Ia, and the processes that lead to their ignition, have not been identified. Two broad classes of progenitor binary systems have long been considered: single-degenerate (SD), in which a WD gains mass from a nondegenerate star; and double-degenerate (DD), involving the merger of two WDs. New theoretical work has enriched these possibilities with some interesting updates and variants. We review the significant recent observational progress in addressing the progenitor problem. We consider clues that have emerged from the observed properties of the various proposed progenitor populations, from studies of SN Ia sites—pre- and postexplosion—from analysis of the explosions themselves and from the measurement of event rates. The recent nearby and well-studied event, SN 2011fe, has been particularly revealing. The observational results are not yet conclusive and sometimes prone to competing theoretical interpretations. Nevertheless, it appears that DD progenitors, long considered the underdog option, could be behind some, if not all, SNe Ia. We point to some directions that may lead to future progress.
Viroids: Survivors from the RNA World?
Authors: Flores Ricardo , Gago-Zachert Selma , Serra Pedro , Sanjuán Rafael , Elena Santiago F.
Published: June 2014

Because RNA can be a carrier of genetic information and a biocatalyst, there is a consensus that it emerged before DNA and proteins, which eventually assumed these roles and relegated RNA to intermediate functions. If such a scenario—the so-called RNA world—existed, we might hope to find its relics in our present world. The properties of viroids that make them candidates for being survivors of the RNA world include those expected for primitive RNA replicons: (a) small size imposed by error-prone replication, (b) high G + C content to increase replication fidelity, (c) circular structure for assuring complete replication without genomic tags, (d) structural periodicity for modular assembly into enlarged genomes, (e) lack of protein-coding ability consistent with a ribosome-free habitat, and (f) replication mediated in some by ribozymes, the fingerprint of the RNA world. With the advent of DNA and proteins, those protoviroids lost some abilities and became the plant parasites we now know.
Prokaryotic Ubiquitin-Like Protein Modification
Authors: Maupin-Furlow Julie A.
Published: June 2014

Prokaryotes form ubiquitin (Ub)-like isopeptide bonds on the lysine residues of proteins by at least two distinct pathways that are reversible and regulated. In mycobacteria, the C-terminal Gln of Pup (prokaryotic ubiquitin-like protein) is deamidated and isopeptide linked to proteins by a mechanism distinct from ubiquitylation in enzymology yet analogous to ubiquitylation in targeting proteins for destruction by proteasomes. Ub-fold proteins of archaea (SAMPs, small archaeal modifier proteins) and Thermus (TtuB, tRNA-two-thiouridine B) that differ from Ub in amino acid sequence, yet share a common β-grasp fold, also form isopeptide bonds by a mechanism that appears streamlined compared with ubiquitylation. SAMPs and TtuB are found to be members of a small group of Ub-fold proteins that function not only in protein modification but also in sulfur-transfer pathways associated with tRNA thiolation and molybdopterin biosynthesis. These multifunctional Ub-fold proteins are thought to be some of the most ancient of Ub-like protein modifiers.
The Peculiarities and Paradoxes of Plasmodium Heme Metabolism
Authors: Sigala Paul A. , Goldberg Daniel E.
Published: June 2014

For over a century, heme metabolism has been recognized to play a central role during intraerythrocytic infection by Plasmodium parasites, the causative agent of malaria. Parasites liberate vast quantities of potentially cytotoxic heme as a by-product of hemoglobin catabolism within the digestive vacuole, where heme is predominantly sequestered as inert crystalline hemozoin. Plasmodium spp. also utilize heme as a metabolic cofactor. Despite access to abundant host-derived heme, parasites paradoxically maintain a biosynthetic pathway. This pathway has been assumed to produce the heme incorporated into mitochondrial cytochromes that support electron transport. In this review, we assess our current understanding of the love-hate relationship between Plasmodium parasites and heme, we discuss recent studies that clarify several long-standing riddles about heme production and utilization by parasites, and we consider remaining challenges and opportunities for understanding and targeting heme metabolism within parasites.
The Importance of Microbes in Animal Development: Lessons from the Squid-Vibrio Symbiosis
Authors: McFall-Ngai Margaret J.
Published: June 2014

Developmental biology is among the many subdisciplines of the life sciences being transformed by our increasing awareness of the role of coevolved microbial symbionts in health and disease. Most symbioses are horizontally acquired, i.e., they begin anew each generation. In such associations, the embryonic period prepares the animal to engage with the coevolved partner(s) with fidelity following birth or hatching. Once interactions are underway, the microbial partners drive maturation of tissues that are either directly associated with or distant from the symbiont populations. Animal alliances often involve complex microbial communities, such as those in the vertebrate gastrointestinal tract. A series of simpler-model systems is providing insight into the basic rules and principles that govern the establishment and maintenance of stable animal-microbe partnerships. This review focuses on what biologists have learned about the developmental trajectory of horizontally acquired symbioses through the study of the binary squid-vibrio model.
Predisposition in Plant Disease: Exploiting the Nexus in Abiotic and Biotic Stress Perception and Response
Authors: Bostock Richard M. , Pye Matthew F. , Roubtsova Tatiana V.
Published: June 2014

Predisposition results from abiotic stresses occurring prior to infection that affect susceptibility of plants to disease. The environment is seldom optimal for plant growth, and even mild, episodic stresses can predispose plants to inoculum levels they would otherwise resist. Plant responses that are adaptive in the short term may conflict with those for resisting pathogens. Abiotic and biotic stress responses are coordinated by complex signaling networks involving phytohormones and reactive oxygen species (ROS). Abscisic acid (ABA) is a global regulator in stress response networks and an important phytohormone in plant-microbe interactions with systemic effects on resistance and susceptibility. However, extensive cross talk occurs among all the phytohormones during stress events, and the challenge is discerning those interactions that most influence disease. Identifying convergent points in the stress response circuitry is critically important in terms of understanding the fundamental biology that underscores the disease phenotype as well as translating research to improve stress tolerance and disease management in production systems.
Plant Cell Wall–Degrading Enzymes and Their Secretion in Plant-Pathogenic Fungi
Authors: Kubicek Christian P. , Starr Trevor L. , Glass N. Louise
Published: June 2014

Approximately a tenth of all described fungal species can cause diseases in plants. A common feature of this process is the necessity to pass through the plant cell wall, an important barrier against pathogen attack. To this end, fungi possess a diverse array of secreted enzymes to depolymerize the main structural polysaccharide components of the plant cell wall, i.e., cellulose, hemicellulose, and pectin. Recent advances in genomic and systems-level studies have begun to unravel this diversity and have pinpointed cell wall–degrading enzyme (CWDE) families that are specifically present or enhanced in plant-pathogenic fungi. In this review, we discuss differences between the CWDE arsenal of plant-pathogenic and non-plant-pathogenic fungi, highlight the importance of individual enzyme families for pathogenesis, illustrate the secretory pathway that transports CWDEs out of the fungal cell, and report the transcriptional regulation of expression of CWDE genes in both saprophytic and phytopathogenic fungi.
Data Visualization in Sociology
Authors: Healy Kieran , Moody James
Published: June 2014

Visualizing data is central to social scientific work. Despite a promising early beginning, sociology has lagged in the use of visual tools. We review the history and current state of visualization in sociology. Using examples throughout, we discuss recent developments in ways of seeing raw data and presenting the results of statistical modeling. We make a general distinction between those methods and tools designed to help explore data sets and those designed to help present results to others. We argue that recent advances should be seen as part of a broader shift toward easier sharing of code and data both between researchers and with wider publics, and we encourage practitioners and publishers to work toward a higher and more consistent standard for the graphical display of sociological insights.
Incarceration, Prisoner Reentry, and Communities
Authors: Morenoff Jeffrey D. , Harding David J.
Published: June 2014

Since the mid-1970s, the United States has experienced an enormous rise in incarceration and accompanying increases in returning prisoners and in postrelease community correctional supervision. Poor urban communities are disproportionately impacted by these phenomena. This review focuses on two complementary questions regarding incarceration, prisoner reentry, and communities: (a) whether and how mass incarceration has affected the social and economic structure of American communities, and (b) how residential neighborhoods affect the social and economic reintegration of returning prisoners. These two questions can be seen as part of a dynamic process involving a pernicious feedback loop in which mass incarceration undermines the structure and social organization of some communities, thus creating more criminogenic environments for returning prisoners and further diminishing their prospects for successful reentry and reintegration.
Ethnic Diversity and Its Effects on Social Cohesion
Authors: Meer Tom van der , Tolsma Jochem
Published: June 2014

Recent years have seen a sharp increase in empirical studies on the constrict claim: the hypothesized detrimental effect of ethnic diversity on most if not all aspects of social cohesion. Studies have scrutinized effects of different measures of ethnic heterogeneity in different geographical areas on different forms of social cohesion. The result has been a cacophony of empirical findings. We explicate mechanisms likely to underlie the negative relationship between ethnic heterogeneity and social cohesion: the homophily principle, feelings of anomie, group threat, and social disorganization. Guided by a clear conceptual framework, we structure the empirical results of 90 recent studies and observe three patterns. We find that (a) there is consistent support for the constrict claim for aspects of social cohesion that are spatially bounded to neighborhoods, (b) support for the constrict claim is more common in the United States than in other countries, and (c) ethnic diversity is not related to less interethnic social cohesion. We discuss the implications of these patterns.
Mechanism of UES relaxation initiated by gastric air distension
Authors: Lang Ivan M. , Medda Bidyut K. , Shaker Reza
Published: June 2014

The aim of this study was to determine the mechanism of initiation of transient upper esophageal sphincter relaxation (TUESR) caused by gastric air distension. Cats ( n = 31) were decerebrated, EMG electrodes were placed on the cricopharyngeus, a gastric fistula was formed, and a strain gauge was sewn on the lower esophageal sphincter ( n = 8). Injection of air (114 ± 13 ml) in the stomach caused TUESR ( n = 18) and transient lower esophageal sphincter relaxation (TLESR, n = 6), and this effect was not significantly ( P > 0.05) affected by thoracotomy. Free air or bagged air ( n = 6) activated TLESR, but only free air activated TUESR. Closure of the gastroesophageal junction blocked TUESR (9/9), but not TLESR (4/4), caused by air inflation of the stomach. Venting air from distal esophagus during air inflation of the stomach prevented TUESR ( n = 12) but did not prevent air escape from the stomach to the esophagus ( n = 4). Rapid injection of air on the esophageal mucosa always caused TUESR (9/9) but did not always (7/9) cause an increase in esophageal pressure. The time delay between the TUESR and the rapid air pulse was significantly more variable ( P < 0.05) than the time delay between the rapid air pulse and the rise in esophageal pressure. We concluded that the TUESR caused by gastric air distension is dependent on air escape from the stomach, which stimulates receptors in the esophagus, but is not dependent on distension of the stomach or esophagus, or the TLESR. Therefore, the TUESR caused by gastric air distension is initiated by stimulation of receptors in the esophageal mucosa.
Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans
Authors: Wojtal Kacper A. , Cee Alexandra , Lang Silvia , Götze Oliver , Frühauf Heiko , Geier Andreas , Pastor-Anglada Marçal , Torres-Torronteras Javier , Martí Ramon , Fried Michael , Lutz Thomas A. , Maggiorini Marco , Gassmann Max , Rogler Gerhard , Vavricka Stephan R.
Published: June 2014

Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals ( n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans.
High-protein diet modifies colonic microbiota and luminal environment but not colonocyte metabolism in the rat model: the increased luminal bulk connection
Authors: Liu Xinxin , Blouin Jean-Marc , Santacruz Arlette , Lan Annaïg , Andriamihaja Mireille , Wilkanowicz Sabina , Benetti Pierre-Henri , Tomé Daniel , Sanz Yolanda , Blachier François , Davila Anne-Marie
Published: June 2014

High-protein diets are used for body weight reduction, but consequences on the large intestine ecosystem are poorly known. Here, rats were fed for 15 days with either a normoproteic diet (NP, 14% protein) or a hyperproteic-hypoglucidic isocaloric diet (HP, 53% protein). Cecum and colon were recovered for analysis. Short- and branched-chain fatty acids, as well as lactate, succinate, formate, and ethanol contents, were markedly increased in the colonic luminal contents of HP rats ( P < 0.05 or less) but to a lower extent in the cecal luminal content. This was associated with reduced concentrations of the Clostridium coccoides and C. leptum groups and Faecalibacterium prausnitzii in both the cecum and colon ( P < 0.05 or less). In addition, the microbiota diversity was found to be higher in the cecum of HP rats but was lower in the colon compared with NP rats. In HP rats, the colonic and cecal luminal content weights were markedly higher than in NP rats ( P < 0.001), resulting in similar butyrate, acetate, and propionate concentrations. Accordingly, the expression of monocarboxylate transporter 1 and sodium monocarboxylate transporter 1 (which is increased by higher butyrate concentration) as well as the colonocyte capacity for butyrate oxidation were not modified by the HP diet, whereas the amount of butyrate in feces was increased ( P < 0.01). It is concluded that an increased bulk in the large intestine content following HP diet consumption allows maintenance in the luminal butyrate concentration and thus its metabolism in colonocytes despite modified microbiota composition and increased substrate availability.
Individual susceptibility to hypoperfusion and reductions in exercise performance when perfusion pressure is reduced: evidence for vasodilator phenotypes
Authors: Bentley Robert F. , Kellawan J. Mikhail , Moynes Jackie S. , Poitras Veronica J. , Walsh Jeremy J. , Tschakovsky Michael E.
Published: June 2014

The primary objective of this study was to determine whether cardiovascular compensatory response phenotypes exist in the face of a reduced perfusion pressure challenge to exercising muscle oxygen delivery (O2D), and whether these responses might be exercise intensity (EI) dependent. Ten healthy men (19.5 ± 0.4 yr) completed two trials of progressive forearm isometric handgrip exercise to exhaustion (24.5 N increments every 3.5 min) in each of forearm above and below heart level [forearm arterial perfusion pressure (FAPP) difference of 29.5 ± 0.97 mmHg]. At the end of each EI, measurements of forearm blood flow (FBF; ml/min) via brachial artery Doppler and echo ultrasound, mean arterial blood pressure (MAP; mmHg) via finger photoplethysmography, and exercising forearm venous effluent via antecubital vein catheter revealed distinct cardiovascular response groups: n = 6 with compensatory vasodilation vs. n = 4 without compensatory vasodilation. Compensatory vasodilators were able to blunt the perfusion pressure-evoked reduction in submaximal O2D in the arm-above-heart condition, whereas nonvasodilators did not (−22.5 ± 13.6 vs. −65.4 ± 14.1 ml O2/min; P < 0.05), and in combination with being able to increase O2 extraction, nonvasodilators defended submaximal V̇o2 and experienced less of an accumulated submaximal O2D deficit (−80.7 ± 24.7 vs. −219.1 ± 36.0 ml O2/min; P < 0.05). As a result, the compensatory vasodilators experienced less of a compromise to peak EI than nonvasodilators (−24.5 ± 3.5 N vs. −52.1 ± 8.9 N; P < 0.05). In conclusion, in the forearm exercise model studied, vasodilatory response phenotypes exist that determine individual susceptibility to hypoperfusion and the degree to which aerobic metabolism and exercise performance are compromised.
Peak exercise oxygen uptake during and following long-duration spaceflight
Authors: Moore Alan D. , Downs Meghan E. , Lee Stuart M. C. , Feiveson Alan H. , Knudsen Poul , Ploutz-Snyder Lori
Published: June 2014

This investigation was designed to measure aerobic capacity (V̇o2peak) during and after long-duration International Space Station (ISS) missions. Astronauts (9 males, 5 females: 49 ± 5 yr, 77.2 ± 15.1 kg, 40.6 ± 6.4 ml·kg−1·min−1 [mean ± SD]) performed peak cycle tests ∼90 days before flight, 15 days after launch, every ∼30 days in-flight, and on recovery days 1 (R + 1), R + 10, and R + 30. Expired metabolic gas fractions, ventilation, and heart rate (HR) were measured. Data were analyzed using mixed-model linear regression. The main findings of this study were that V̇o2peak decreased early in-flight (∼17%) then gradually increased during flight but never returned to preflight levels. V̇o2peak was lower on R + 1 and R + 10 than preflight but recovered by R + 30. Peak HR was not different from preflight at any time during or following flight. A sustained decrease in V̇o2peak during and/or early postflight was not a universal finding in this study, since seven astronauts were able to attain their preflight V̇o2peak levels either at some time during flight or on R + 1. Four of these astronauts performed in-flight exercise at higher intensities compared with those who experienced a decline in V̇o2peak, and three had low aerobic capacities before flight. These data indicate that, while V̇o2peak may be difficult to maintain during long-duration ISS missions, aerobic deconditioning is not an inevitable consequence of long-duration spaceflight.
Chromosomal Instability Selects Gene Copy-Number Variants Encoding Core Regulators of Proliferation in ER+ Breast Cancer
Authors: Endesfelder David , Burrell Rebecca A. , Kanu Nnennaya , McGranahan Nicholas , Howell Mike , Parker Peter J. , Downward Julian , Swanton Charles , Kschischo Maik
Published: June 2014

Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor–positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation. Cancer Res; 74(17); 4853–63. ©2014 AACR.
Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis
Authors: Boyango Ilanit , Barash Uri , Naroditsky Inna , Li Jin-Ping , Hammond Edward , Ilan Neta , Vlodavsky Israel
Published: June 2014

Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development. Cancer Res; 74(16); 4504–14. ©2014 AACR.
Case–Control Study of Aspirin Use and Risk of Pancreatic Cancer
Authors: Streicher Samantha A. , Yu Herbert , Lu Lingeng , Kidd Mark S. , Risch Harvey A.
Published: June 2014

Background: Pancreas-cancer prognosis is dismal, with 5-year survival less than 5%. Significant relationships between aspirin use and decreased pancreas-cancer incidence and mortality have been shown in four of 13 studies.

Methods: To evaluate further a possible association between aspirin use and risk of pancreatic cancer, we used data from a population-based Connecticut study conducted from January 2005 to August 2009, of 362 pancreas-cancer cases frequency matched to 690 randomly sampled controls.

Results: Overall, regular use of aspirin was associated with reduced risk of pancreatic cancer [odds ratio (OR), 0.52; 95% confidence interval (CI), 0.39–0.69]. Increments of decreasing risk of pancreatic cancer were observed for each year of low-dose or regular-dose aspirin use (OR, 0.94; 95% CI, 0.91–0.98 and OR, 0.98; 95% CI, 0.96–1.01, respectively) and for increasing years in the past that low-dose or regular-dose aspirin use had started (OR, 0.95; 95% CI, 0.92–0.99 and OR, 0.98; 95% CI, 0.96–1.00, respectively). Reduced risk of pancreatic cancer was seen in most categories of calendar time period of aspirin use, for both low-dose aspirin and regular-dose aspirin use. Relative to continuing use at the time of interview, termination of aspirin use within 2 years of interview was associated with increased risk of pancreatic cancer (OR, 3.24; 95% CI, 1.58–6.65).

Conclusions: Our results provide some support that a daily aspirin regimen may reduce risk of developing pancreatic cancer.

Impact: Long-term aspirin use has benefits for both cardiovascular disease and cancer, but appreciable bleeding complications that necessitate risk–benefit analysis for individual applications. Cancer Epidemiol Biomarkers Prev; 23(7); 1254–63. ©2014 AACR.
Detection of Minimal Residual Disease in B Lymphoblastic Leukemia by High-Throughput Sequencing of IGH
Authors: Wu David , Emerson Ryan O. , Sherwood Anna , Loh Mignon L. , Angiolillo Anne , Howie Bryan , Vogt Jennifer , Rieder Mark , Kirsch Ilan , Carlson Christopher , Williamson David , Wood Brent L. , Robins Harlan
Published: June 2014

Purpose: High-throughput sequencing (HTS) of immunoglobulin heavy-chain genes (IGH) in unselected clinical samples for minimal residual disease (MRD) in B lymphoblastic leukemia (B-ALL) has not been tested. As current MRD-detecting methods such as flow cytometry or patient-specific qPCR are complex or difficult to standardize in the clinical laboratory, sequencing may enhance clinical prognostication.

Experimental Design: We sequenced IGH in paired pretreatment and day 29 post-treatment samples using residual material from consecutive, unselected samples from the Children's Oncology Group AALL0932 trial to measure MRD as compared with flow cytometry. We assessed the impact of ongoing recombination at IGH on MRD detection in post-treatment samples. Finally, we evaluated a subset of cases with discordant MRD results between flow cytometry and sequencing.

Results: We found clonal IGH rearrangements in 92 of 98 pretreatment patient samples. Furthermore, while ongoing recombination of IGH was evident, index clones typically prevailed in MRD-positive post-treatment samples, suggesting that clonal evolution at IGH does not contribute substantively to tumor fitness. MRD was detected by sequencing in all flow cytometry–positive cases with no false-negative results. In addition, in a subset of patients, MRD was detected by sequencing, but not by flow cytometry, including a fraction with MRD levels within the sensitivity of flow cytometry. We provide data that suggest that this discordance in some patients may be due to the phenotypic maturation of the transformed cell.

Conclusion: Our results provide strong support for HTS of IGH to enhance clinical prognostication in B-ALL. Clin Cancer Res; 20(17); 4540–8. ©2014 AACR.
Antineutrophil Cytoplasmic Antibodies in Patients with Idiopathic Inflammatory-Demyelinating Diseases
Authors: Long Youming , Zheng Yangbo , Chen Mengyu , Zhang Bin , Gao Cong , Gao Qingchun , Yin Jian-rui , Pu Shuxiang , Xie Changlong
Published: June 2014

Objective: We assessed the clinical significance of antineutrophil cytoplasm antibodies (ANCA) in patients with idiopathic inflammatory-demyelinating disease (IIDD). Methods: A consecutive cohort of 269 subjects with IIDD and 595 controls was analyzed retrospectively. Results: Among all subjects, ANCA positivity rates were low [9.5% in a perinuclear pattern (pANCA) and 2.3% in a cytoplasmic pattern (cANCA)]. One of the 117 patients with multiple sclerosis (MS) had cANCA and 2 had pANCA. Ten patients with neuromyelitis optica (NMO; 13.9%) had pANCA and 3 (4.2%) had cANCA. Four patients with recurrent longitudinal extensive transverse myelitis (RLETM; 19.0%) had pANCA and 1 (4.8%) had cANCA. In monophasic TM, 22.9% were pANCA seropositive. Among patients with brainstem syndromes, 14.3% were pANCA seropositive. Patients with NMO, RLETM or monophasic TM had higher pANCA levels than patients with MS. There was a positive association between spinal cord (SC) lesions and ANCA, and especially between longitudinal extensive transverse myelitis and ANCA. Among anti-aquaporin 4 antibody-positive patients, ANCA-positive patients (n = 16) were older and had higher Expanded Disability Status Scale scores, more antinuclear antibodies, longer SC lesions and fewer brain abnormalities than the ANCA-negative patients (n = 68). In the NMO subgroup, ANCA-positive patients were older and had more antinuclear antibodies and longer SC lesions than ANCA-negative patients. Conclusion: Among the IIDDs, we found a higher occurrence of ANCA in patients with NMO spectrum disorders than in patients with MS. Therefore, ANCA is another interesting marker of autoimmunity in IIDD patients, especially those with anti-aquaporin 4 antibody.
Comparison of the Outcomes of Photodynamic Therapy between Two Angiographic Subtypes of Polypoidal Choroidal Vasculopathy
Authors: Honda Shigeru , Miki Akiko , Yanagisawa Suiho , Matsumiya Wataru , Nagai Takayuki , Tsukahara Yasutomo
Published: June 2014

Background: To compare the outcomes of photodynamic therapy (PDT) between two different angiographic subtypes of polypoidal choroidal vasculopathy (PCV). Methods: Ninety-three consecutive cases of PCV were classified into two phenotypes (42 type 1 and 51 type 2) according to the presence or absence of feeding vessels found on indocyanine green angiography. Full-dose PDT and retreatments were performed every 3 months as needed based on the findings on angiography. The best-corrected visual acuity (BCVA) was compared as the main outcome between type 1 and type 2 PCV up to 12 months after the initial PDT. Results: The baseline greatest linear dimension (GLD) was significantly larger in type 1 PCV than type 2 PCV. The mean BCVA was significantly improved from baseline in type 2 PCV, while no improvement was found in type 1 PCV. Analysis with matching the GLD between both PCV subtypes did not change the original results. Conclusions: There may be a significantly different response to PDT between two angiographic phenotypes of PCV.